The film is a sequel to Cats & Dogs (2001) which was an amusing but largely forgettable family flick that had domestic canines and felines running a secret war against each other. In this film the Cats and Dogs continue to be mortal enemies in a battle for supremacy among humans, and both sides have secret organizations and technology at their disposal.
A loose -cannon police dog named Diggs (voice of James Marsden) is recruited by his species' equivalent of the CIA to help stop a psychotic hairless cat named Kitty Galore (Bette Midler). Kitty plans to deploy a weapon that will make all dogs go crazy, which will cause their owners to get rid of them, which will enable cats to take over their share of the pet market.
The feline intelligence agency wants to stop the rogue Kitty, too, as her actions would upset the balance of power and violate the rules of war, or something. This leads to a rare truce between cats and dogs so the two sides can work together and thwart their common enemy. Diggs and his gruff veteran partner, Butch (Nick Nolte), are teamed with Catherine (Christina Applegate), a top feline spy. They receive intel from a stool pigeon named Seamus (Katt Williams). They also descend into a Silence of the Lambs-ish prison to seek advice from Mr. Tinkles (Sean Hayes), the fiendish feline villain from the first Cats & Dogs.