The movie begins with a little white dog tied up on a city street. Images pop up, as he smells different things. He smells a hot dog, escapes from his collar and goes down the street until he finds a guy eating one. The guy teases him, and then gets splashed and the dog gets his food. We then see Bruce (Jake T. Austin) on the floor of a restroom, shrink-wrapping a box that his sister Andi (Emma Roberts) pawns for cash. They meet in a park, where they have used the money to feed the white dog, Friday. Suddenly, they see the police with the pawnshop employee who points her out as the scammer. She tries to get out of it but Bruce spills his backpack, revealing his scamming supplies. Busted.
Bernie (Don Cheadle), their social worker, meets them at the station and is disappointed, warning them that they have been in too many foster homes and next time they may have to be separated. He returns them to their foster parents (Lisa Kudrow and Matt Dillon) who are annoyed that the two have missed their dinner and delayed their band practice. Bernie claims responsibility and does not tell them about the arrest. They go to their room where Friday appears at the window. They hide Friday from Bernie and Bruce goes to sleep cuddling him.
In the morning, Friday has gone into the apartment where the foster mother almost sees him several times before the kids get him into the bedroom, where he has his own dog-operated elevator to the ground. He wanders around following smells before Animal Control picks him up. The kids try calling him, the canvass the neighborhood. They stop into a pet store, where they meet Dave (Johnny Simmons) and Heather (Kyla Pratt). Dave suggests they try the pound. Friday is there, but Andi to bribe them to get him out. On the way home, they witness a break-in. Police pull up, and afraid of being blamed, they run. Friday wiggles into the door of the abandoned Drake Hotel, and the kids follow. They hear scary sounds, which turn out to be two dogs that are friendly. They go upstairs, and see the dogs comfy on a bed, and decide that Friday is safe there for the night. Andi pulls down the shade.
They wake to the sound of loud howling. People in the neighborhood are calling the police. Andi and Bruce know what it is, and are trying to steal food to take to the dogs, but the foster mother catches them and insists they eat it all. They manage to hide it and get out. At the hotel, they find the large dog is upset about the closed shade.
Andi returns to the pet store for more food, tells Dave a lie about having parents and being dog rescuers and is forced to take the unwanted dogs in the back of the store. They return to the hotel where Heather follows them and says she wants to help. Mark (Troy Gentile), who works nearby also turns up and joins the group. Bruce invents several things that feed the dogs, entertain them and take care of their waste. They form a rescue team that rescues more strays before animal control can get them.
Bernie comes to their apartment and tells them he has a great couple that wants them, but they live 3 hours away. The kids turn him down, saying they like their friends. He does not understand, but he lets them go.
Andi is invited to a party with her future classmates. She runs into someone who recognizes her and reveals to Dave and Heather that she is a foster kid. She gets upset, crashes into someone carrying drinks, is humiliated and runs to the hotel, where Bruce is there, trying to manage the chaos of all the inventions going haywire and the dogs running wild. The police burst in and take the kids and dogs in custody as their friends watch. Bernie and his wife Carol (Robinne Lee) are there and explain that they have tried but there is nothing more they can do. Andi apologizes but Bruce says he would not do it differently. The kids each go to group homes, and we see that the dogs are scheduled for termination.
Andi is surprised by seeing Friday, with Dave outside her home, where he says he has a plan to get the dogs. They rescue Bruce, and Mark is dressed as a commando in the back of the van. Heather tricks the animal control guy into coming outside, where they sneak in, lock him out and release the dogs. They try to lead the dogs across the county line but at the last moment, Friday smells his old bed at the hotel and leads all the dogs back. There is a big standoff with animal control and police with lots of media. Bernie appears at the top of the steps, gets everyone's attention and gives a moving speech where he introduces all the dogs by name and history by reading the hotel's register. The news reporters are interested and convince the police to let them in. Bernie tells the kids that he has found adoptive parents for them, meaning himself. Andi and Dave kiss.
The hotel is now restored thanks to donations from the people of the city, where dogs get all kinds of first class treatment. We see all the friends there working, and the dogs have jobs there too. The former foster parents are performing their music in the lounge. The kids and Friday are having dinner with Bernie and Carol in the roof garden.
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