David Barclay served as animatronic effects supervisor. Puppeteers included Adam Behr, Kevin Carlson, Alejandro Diaz, Randi Kaplan, John Kennedy, Luke Khanlian, Bruce Lanoil (lead performer for Mr. Tinkles), Drew Massey, Gord Robertson, Michelan Sisti, and Allan Trautman (lead puppeteer for Calico). Marian Keating and Julie Zobel were senior fabricators, and Rob Hinderstein supplied eyes, teeth, and tongues.
The 2010 sequel, Cats & Dogs: The Revenge of Kitty Galore, did not have involvement of the Creature Shop. Instead, Lee Romaire Studios provided the creatures. David Barclay was once again the animatronic effects supervisor.
Mrs. Carolyn Brody (Elizabeth Perkins) and her son Scott (Alexander Pollock) return home and the family's Bloodhound Buddy starts chasing a cat, a chase which ends with Buddy's capture by other cats in an ambush.
This is witnessed by Anatolian Shepherd dog named Butch (voiced by Alec Baldwin) who reports Buddy's capture to his superiors. The head dog then orders the best canine agents to complete the mission by preventing all (cats) from achieving their favorite goal: to make all humans allergic to dogs.
Meanwhile, at a farm, a handful of Beagle puppies make fun of a younger puppy (voiced by Tobey Maguire), who wants to be free. The younger puppy tries an escape, but he fails. A group of young black Doberman puppies, all of them trained dog agents, led by a large Doberman Pinscher appear, round up the Beagle puppies and force them into hiding underground. Mrs. Brody comes into the puppy pen and she selects the younger puppy who was forgotten by the Dobermanns. She decides to adopt him and takes him home, naming him Lou after Scott sarcastically suggests the name "Loser".
Lou goes near an explosive trap set by the cats but Butch comes out and detonates it harmlessly. Butch then shows Lou the network that dog agents use, then takes him to meet some more agents: Peek (voiced by Joe Pantoliano) is a Chinese Crested Dog who works in an underground tube and has surveillance and communications equipment and Sam (voiced by Michael Clarke Duncan) who is an Old English Sheepdog. Having mistaken Lou for a trained dog agent, Butch raises his concerns to his superiors, but is told that there is no time to send a replacement. Lou is then briefed on the origins of the war between cats and dogs, which apparently dates all the way back to Ancient Egypt. Butch also mentions that fate of Buddy, who meanwhile had managed to escape from the cats and was now retired from the spy business, living life in a condominium.
Meanwhile, Mr. Tinkles (voiced by Sean Hayes), a white Persian cat, plans to conquer the world by making all humans allergic to dogs with Mr. Brody (Jeff Goldblum)'s research on a cure for dog allergies. He is briefly interrupted by Sophie the Maid (Miriam Margoyles) who needs to dress him upon seeing the comatose Mr. Mason (Myron Natwick). Tinkles then tells his sidekick Calico (voiced by Jon Lovitz), an Exotic Shorthair, to send in the ninja cats (voiced by Danny Mann and Billy West) he hired to steal the research. He sends in the Devon Rex ninjas but Lou manages to prevent the theft. Lou then meets a former agent and Butch's ex-sweetheart and girlfriend named Ivy (voiced by Susan Sarandon), a Saluki who belly scratches him. Disappointed that the ninja cats failed him, Mr. Tinkles then orders Calico to send a Russian Blue mercenary, whose name is Diemitir Kennelkoff, (voiced by Glenn Ficarra) to steal the research. Kennelkoff frames Lou for defecating in the house with a ball containing fake dog feces, causing Lou to be confined outside, then places a bomb on the lab door. Butch and Lou manage to get into the house through the window, but Peek and Sam are trapped outside after Lou knocks the window prop away. Kennelkoff fires a series of boomerangs around the Brodys' house causing serious damage and which break several vases and knock a lamp over; the boomerangs also cause the curtain pole to break. Lou then distracts the Russian while Butch tries to disable the bomb, but Kennelkoff turns his attention on Butch and tries to kill him. Butch gets caught in a telephone wire, then Mrs Brody comes home looking for her cell phone and surprisingly does not notice her wrecked living room. Although he suspects that dogs can see in black and white, Butch manages to escape and disables the bomb, but Kennelkoff holds out a remote that will detonate the bomb and laughs until the lab door opens and hits him. Kennelkoff is then captured and interrogated. The agent tells the gang that they pumped a few things out of Kennelkoff's stomach, including a note written by Mr. Tinkles.
After an incident involving Lou playing with Scott, Professor Brody's machine finally gets the positive combinations for the formula. As Mr. Tinkles and Calico overhear the call between Professor Brody and a doctor, they decide to spring a trap for Dr. Brody and his family. First, Mr. Tinkles makes his sinister and talking side known to Sophie, causing her to faint, then he and his cats take Mr Mason's comatose body to Mason's Christmas tree flocking plant, where Tinkles passes his voice off as Mr Mason to send the employees home and commandeer the factory for the next plot. The cats send soccer tickets to an exhibition game between Uruguay and Chad to the Brody family, obviously a ruse. The cats make a fake entry and when the Brody family pulls up, the cats throw a gas bomb into their car, which goes off in a tremendous explosion and leaves the family unconscious.
While trying to decipher Mr. Tinkles's location, the dogs are obviously unaware that the Brodys have been led into a trap and are kidnapped by the said cat. After receiving a video from the cat demanding Mr. Brody's research as a ransom, the dogs from around the world assemble at a meeting (like the United Nations General Assembly) run by the Mastiff (voiced by Charlton Heston). When the dog agents are unable to give up the formula after the meeting of the world's dogs, Lou angrily confronts Butch for not helping him. Butch then explains that when his owner went to college, he left him with his grandmother and storms off, cutting off all of Lou's communications with Peek and the others so Lou would not seek help to save his family. Lou gives in and brings Mr. Tinkles the research and is betrayed. Butch manages to find the depressed Lou and, along with Ivy, the two stage an ambush of Mr. Tinkles's factory where the latter plans to use mice to spread the now mass-produced allergy to dogs. While Butch, Ivy, Peek, and Sam fight Tinkles's cat forces, Lou frees the Brodys and Calico (who was betrayed by Tinkles), revealing he can speak in the process. Lou defeats Tinkles and rescues Butch, but the claw of the excavator hits his head and a flocking tank, causing an explosion that destroys the factory. Butch manages to save Lou, but the latter is unresponsive. After a few hurtful moments of sadness and sorrow; in which Scott, feeling genuinely sorry and remorseful for referring to Lou as loser, tearfully apologizes to Lou; Lou suddenly awakens and all rejoice. Lou decides to be a normal canine and not a secret agent yet, but one day he will be when he is a full-grown beagle.
Meanwhile, Mr. Tinkles is sent to live with Sophie and her three sisters, who dress him in hilariously ridiculous girly outfits.
- Jeff Goldblum as Jeff Goldblum
- Elizabeth Perkins as Mrs. Goldblum
- Alexander Pollock as Scotty Goldbum
- Miriam Margolyes as Sophie
- Tobey Maguire/Spider-Man as Tobey Maguire/Spider-Man (voice)
- Alec Baldwin as Alec Baldwin (voice)
- Sean Hayes as Sean Hayes(voice)
- Susan Sarandon as Susan Sarandon (voice)
- Joe Pantoliano as Joe Pantolianovoice)
- Michael Clarke Duncan as Michael Clarke Duncan (voice)
- Jon Lovitz as Jon Lovitz (voice)
- Myron Natwick as Mr. Mason
- Victor Wilson as Victor Wilson (voice)
- Salome Jens as Salome Jens (voice)
- Danny Mann and Billy West as Danny Mann and Billy West (voice)
- Paul Pape as Paul Rape(voice)