The show revolves around Buddy, a beagle separated from his 10-year-old owner Jeffy in Elizabeth, New Jersey, and Woof, a large bulldog (to whom Buddy refers as obsessed) who runs away from his owner. Both canines try to survive in the streets of Hollywood and avoid conflict with the Dog Catcher. The show bombards celebrity stardom in various ways; for example, many of the characters based on real celebrities have other voice actors impersonating their voices (such as Steve-O from Jackass and Wildboyz, who appeared in the third episode).
Buddy and Woof get a celebrity treatment from Lindsay Lohan and are adopted by Angelina Jolie and Brad Pitt, but canines are having trouble with Maddox.
Buddy and Woof break out of the Hollywood Dog Pound and try to get on TV at the MTV Movie Awards (which is hosted by Jimmy Fallon after Dave Chappelle got injured in the intro), since Buddy's owner watches every year and will hopefully see him. Unfortunately for Buddy and Woof, the Dog Catcher is attending the MTV Movie Awards. Celebrities mocked include Paris Hilton, 50 Cent, Jimmy Fallon, Andy Dick, Jack Black, and Jessica Simpson. Other celebrities mocked include Eminem. Other celebrities mocked with non-speaking roles include Tony Yayo, Lloyd Banks & Young Buck.
Buddy and Woof go to the Hollywood Celebrity Dog Park, where they end up being taken home by Bobby Brown and Whitney Houston.
Buddy and Woof get adopted by Snoop Dogg. Buddy's excited that Snoop's upcoming tour with Eminem will go to Jersey, only to find Snoop retiring from rap. Buddy and Woof then conspire to get Snoop back in the rap game by creating a feud with Snoop's next door neighbor, Hilary Duff.
After Tara Reid announces the official end of her career, Buddy and Woof end up at a rehab facility with her. That's where they meet Mariah Carey, Russell Crowe and Janet Jackson, as well as Andy Dick, who helps the dogs escape.
The dogs want to move into Michael Jackson's abandoned Neverland Ranch, but first they must fight off PETA and Jennifer Lopez.
Vince Vaughn gives the dogs to girlfriend Jennifer Aniston to keep her company while he's off making a movie. She and Buddy go on the computer and learn about MePlace.com.
Buddy is kidnapped by Tom Cruise, who plans to sacrifice him in a Scientology ritual. A group of Kabbalists rescues Buddy, and Ashton Kutcher and Demi Moore take the dogs home. The dogs end up doing stunt work for Bruce Willis, but Cruise comes back for Buddy, starting a clash between the Scientologists and Kabbalists.