David Clarke (Jason Sudeikis) is sitting on his couch watching funny YouTube videos before he starts getting hit up for weed. He goes around town making the deliveries while scoring a pretty sweet amount of cash. That evening, David runs into an old college friend named Rick Nathanson (Thomas Lennon). Rick mentions his life as a family man and wonders why David hasn't gotten around to settling down. David gives him some pot as a gift and sends him off.
Rose O'Reilly (Jennifer Aniston) is at her job at the strip joint. She's talking to a particularly dim co-stripper named Kymberly (Laura-Leigh), who tells her that her stage name is "Boner Garage" (with a tattoo pointing down below to prove it). Their boss Todd (Ken Marino) tells Rose to go tend to a customer with two hook hands.
David and Rose meet up at their apartment. David tries to start some small talk, but Rose is not interested in anything he has to say and does not even consider him a neighbor. He hands her a bit of her mail that he got, reminding her that her rent is due. As Rose goes to her apartment, a dorky kid named Kenny (Will Poulter) comes in to say hi to David and also asks to buy weed, but he refuses to sell to him. Outside, Kenny sees some punks harassing a young woman. He tries to be the hero and defend her, but he only gets attacked. David tries to intervene and get Kenny out of there, but he stupidly blabs out to the punks that David is a drug dealer. David and Kenny make a run for it. David runs through a fire escape and tries to throw the money into a dumpster and jump after it, but the dumpster closes and he falls hard on his back. The punks assault him, go to his apartment, and rob him of his entire drug stash and money.
The next morning, David is at a diner where he keeps getting phone calls from someone named Brad Gurdlinger. On his way out, he is tased and captured by two goons. He is taken all the way to the home of Brad (Ed Helms), David's distributor, complete with an aquarium featuring a killer whale. Brad knows David got robbed, but he offers him a chance to redeem himself. He instructs him to go to Mexico to pick up a "smidge (and a half)" of weed for "Pablo Chacon" (Brad's alias) and bring it back by Sunday night, which is 4th of July. Brad also reminds David that he does not have a choice.
David tells Kenny about his dilemma. He suggests using a disguise, but David thinks it's a stupid idea. That's when a family man in an RV pulls up to ask David and Kenny for directions to the zoo. David insults them and tells them to fuck off, but a cop offers directions. That's when the idea hits David, and he comes up with a plan. He runs to the strip joint to ask Rose for help with the plan, in which he will have her pose as his wife so that they can look like a regular family crossing the border to Mexico to pick up the weed without arousing suspicion, and in return, he would give Rose $10,000. Rose adamantly refuses. However, David convinces Kenny to come along just for the ride. He even finds the girl from the night before, Casey (Emma Roberts), and hires her for $1,000, believing her to be homeless.
Rose is told by Todd that he wants her to start having sex with customers for payment, making Rose angry enough to quit. When she gets home, she finds an eviction notice on her door.
David, Kenny, and Casey all head off to the airport the next day to fly down to Mexico, themselves. David introduces the three of them as the Millers. It starts off rocky when Casey makes a snide joke in front of the flight attendant. They are joined by Rose, to David's surprise. As Rose puts her bag in the overhead compartment, Kenny accidentally presses his face against her breasts, which somehow causes him to accidentally smack Casey in the face, inciting an argument among the whole "family". David pulls them all to the back, where he doubts Rose's ability to pull off the act, but she surprises them when she makes them all appear to be praying to throw off suspicion from the flight attendant.
The group arrives in Mexico and is presented with an RV of their own to cross the border. On the road, Casey spots a fireworks stand, so she and Kenny try and beg David, as if they were children, to grab some fireworks. He tells them all straight up that this is just a job and that they are not really a family. However, he goes back to get a single firework to satisfy them.
They manage to get through and head to pick up the weed, arriving at a drug ranch. David says he is picking up for Pablo Chacon, but is alarmed to discover that the "smidge and a half" of weed is actually close to two metric tons. He calls up Brad to complain, but he only mocks him and reminds him to bring it back by Sunday. Meanwhile, Kenny is given a fruit basket by the mother of a one-eyed goon, unaware that a large tarantula is crawling in there.
The group heads back to the border with weed in nearly every compartment where it can be hidden. They are stopped by a cop (Luis Guzman), who remarks that he saw them coming from Pablo Chacon's ranch, and he will not arrest them under the condition of a bribe. He asks for 100,000. Thinking he means the weed, David says they don't have that amount. The cop then suggests that they provide him with an intimate favor. David tells Rose to suck the cop off, but the cop says he is gay. David refuses to do the act and manages to convince Kenny to go through with it for the ladies. The cop comes out as Kenny is preparing himself, but the cop says he meant he wanted 100,000 pesos, which, as David guesses, is roughly 80 American dollars. He gives him $100 and grabs Kenny and leaves.
On the way back to the border, the group passes another family in an RV, the Fitzgeralds - Don (Nick Offerman), Edie (Kathryn Hahn), and their daughter Melissa (Molly Quinn), whom Kenny is instantly smitten with. As they inch closer to the border, they spot a vehicle that is pulled over and caught with a joint. The driver is then viciously assaulted by the officers at the border, alarming the group just as a pound of weed falls in Rose's lap. She quickly covers it up, leading Edie to think she has a baby. David tells the group to calm down and put on sombreros to appear like a family. He drops his smile as he grows nervous. The officer at the front asks the group to step out. Before he can search the RV, a bunch of Mexicans crawl from under the RV and make a run for it. The officer pardons the group since this happens often.
David is ecstatic to have made it out of there, but he drives so fast that he causes the RV to heat up and break down. Rose and Casey walk off in frustration. As they walk down the road, Casey admits to Rose that she is not homeless, but that she prefers to stay with her friends instead of being home. They nearly start arguing when Casey makes a snide remark about Rose's stripping profession, but they are picked up by the Fitzgeralds, who have already picked up David and Kenny (and the pound of weed), along with the broken down RV in tow. On their way to a garage, Edie asks David how he and Rose met. He describes a memory he had of Rose when he admired how she looked, sounding very sincere and genuine, almost touching Rose. He ruins it when he recalls accidentally wrecking a painting done by Rose's grandfather. He also unintentionally discovers that Don is a DEA agent.
The garage turns out to be closed for the night, so the Fitzgeralds resolve for the "Millers" to camp with them for the night. Edie wants to hold Rose's "baby", but Rose panics to the point where she tosses the pound into the street, where it is run over by a truck, scaring the absolute shit out of Edie. Casey saves them when she says this was part of a school experiment.
The real Pablo Chacon (Tomer Sisley) arrives to his ranch to pick up the stash of weed with an average-looking guy with him. When he is told that another "gringo with a haircut like a donkey" has already picked up the weed, Pablo brings his one-eyed goon with him to track the family down.
That evening, during a game of Pictionary, David and Rose plot to steal Don's RV keys while he and Edie are asleep. As Melissa is up to draw, she is upset when her parents can't guess what she's drawing. Kenny goes up to make her feel better with his terrible drawing of a skateboard, which Rose misinterprets as "Black Cock Down". After that disaster of a game, Casey catches Kenny talking to Melissa outside the RV, bringing David and Rose to check out the scene. Melissa tries to get a kiss from Kenny, but he hugs her instead. David goes outside to talk to him, and the best advice he can give him is to count to three in a tense situation.
While the Fitzgeralds are sleeping, David and Rose sneak out to steal the keys. The Fitzgeralds awaken to find the two of them in their tent, but they believe that they are there for a sexual fling. After Edie grabs Rose's breasts for a bit, the pair leaves uncomfortably.
Casey attempts to help Kenny out after learning that he's never kissed a girl. She teaches him how to kiss, out of pity, which David and Rose walk in on. Rose joins in to help Kenny practice, but Melissa walks in on them, making it look like Kenny is kissing his mother and sister. She leaves appalled, and Kenny is flat out embarrassed.
Don and Edie take the group to the garage and drop them off. As David calls Brad up, they are ambushed by Pablo, who found the RV with a tracking device. He plans to kill the group as a family, but David admits that the family is fake and that Rose is just a stripper. This gets Pablo's attention, and he orders Rose to strip. She puts on a very hot show for everybody, ending with her pulling steam on Pablo's face, giving them an opportunity to run. Kenny tries to drive the RV and busts out of the garage and wrecks Pablo's car. On their way out, the tarantula in the fruit basket crawls it's way up to Kenny's leg and bites him, causing him swerve and run the RV off the road. He runs out in pain and reveals to the group a very large and painful-looking swollen testicle, eventually fainting from it.
The group is forced to stick around the hospital for a few hours as Kenny recovers. Casey goes off with a loser named Scottie P. (Mark L. Young) for a few hours while David and Rose briefly bond. Through this, David learns that Rose's real name is Sarah. As Casey comes back, David and Rose chastise her for spending so much time out, almost sounding like a real mother and father.
Kenny is released to the group, and David rushes him off in his wheelchair to the RV, only to knock Kenny down as he hits the RV. David tries to pick him up in the most irresponsible way, upsetting Rose and Casey. This leads to a big argument between everybody, and Casey walks off on her own. David is prepared to leave, but Kenny and Rose won't leave without Casey. David leaves them behind and drives off. As he drives further, he hears "Waterfalls" by TLC on the radio, which Kenny humorously sang along to earlier.
Kenny and Rose find Casey with Scottie P., who tries to sexually harass Casey. They come to her aid, with Kenny counting to three before Rose punches Scottie in the nose, sending him off. David arrives in time to find the three of them, having to get on his knees and beg them to rejoin him (he only really gets on his knees). While they're heading back, they run into Edie and Melissa. Melissa is still uncomfortable with how she saw Kenny the previous night, eventually forcing Kenny to reveal that the family is fake and that they are smuggling pot across the border. That's when the one-eyed goon steps in to kill the group, but, not before Don pops up and completely incapacitates the goon. Unfortunately, Pablo comes out holding Melissa at gunpoint. He plans to kill the whole group, but David steps in to defend them, giving a speech on how he's come to love the three of them and that the Fitzgeralds were in the wrong place at the wrong time. Before Pablo can kill any of them, fireworks are set off, distracting Pablo long enough for David to hit him, throwing the gun out of his hand, and giving Kenny the chance to knock him out cold. This impresses Melissa, but not as much as Kenny grabbing her and kissing her romantically beneath the fireworks (with a tongue trick that Rose taught him). Don arrests Pablo and his goon, and then says that he must also arrest the group...after he hugs his family. The group reads this as a sign that the Fitzgeralds are letting them escape, and they take it.
David finally brings the weed to Brad, but since he missed the deadline, he is not getting paid. Turns out, Brad was actually never going to pay him at all. David turns the tables on Brad when a whole team of DEA agents bursts into Brad's place, arresting him and his guys. Don thanks David for helping him bring Pablo and Brad to them. Don then tells David that he will have to be placed in witness protection for the next 3 to 6 months, along with every other witness to the crime. David smiles.
The group is now living as a family in a pretty nice home. David meets the new neighbors, the Johnsons. He introduces himself, Kenny, Casey, and Rose (calling her Sarah) as the Millers. David and Rose walk away saying they don't like the Johnsons. As they sit to have a meal, it is revealed they are growing marijuana leaves in their backyard.
Bloopers and outtakes are shown before the credits, ending with Jason Sudeikis putting on the "Friends" theme song for Jennifer Aniston, and having Emma Roberts and Will Poulter sing along and clap for fun.
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