PlotDave Douglas (Tim Allen) is a deputy district attorney, whom viewers see prosecuting activists who have broken into and allegedly set fire to the laboratory of pharmaceutical corporation Grant and Strictland, which the activists accuse of deliberately creating genetic freaks while searching for a "Fountain of Youth". This distances Douglas from his activist daughter Carly (Zena Grey).
Viewers learn that the power-hungry minions of Mister Strictland (the surviving but aged junior partner of the late Grant), led by Dr. Kozak (Robert Downey Jr.), have stolen from a Tibetan Buddhist monastery the dog Khyi-yag-po (played by a bearded collie), whose DNA carries a mutation granting an extraordinary lifespan. Seeking to obtain his seeming immortality for themselves, the geneticists carry out several experiments which fail comically; though cell degradation desists in all the test subjects (a bullfrog, rats, a chimpanzee, a cobra, and a capuchin monkey), all of these start behaving like dogs. The scientists determine that Khyi-yag-po's mutation is contagious and transmissible by bodily fluids.
Khyi-yag-po later escapes his cage and is found by Carly Douglas and her friend Trey (Shawn Pyfrom), who are trying to find evidence of the company's animal testing. They bring him home and dub him "Shaggy". When Dave returns from work, he objects to the dog's presence and orders it out, but in the process is bitten on the hand, whereupon Khyi-yag-po's saliva enters Dave's veins, infecting him with the mutation.
Dave thereafter begins to exhibit canine behavior such as eating with only his mouth, being territorial in the presence of other dogs, and licking his wife rather than kissing her. When he becomes excited by stimuli associated with dogs, such as the command "Fetch!" or the presence of a cat, he transforms completely into a replica of Khyi-yag-po. This change is reversed only when he has calmed, as during sleep. When the real Khyi-yag-po is caught by Kozak's lab minions, Dave is mistaken for "Shaggy" and takes his place. His family, ignorant of this, speak freely in his presence, leading Dave to realize that he is estranged from them. In particular, he learns that his son Josh (Spencer Breslin) wants to sing in the musical Grease instead of playing football, but is too scared to tell his father so.
In the ongoing trial, testimony from the activist accused of setting the lab on fire includes a description of the animals behaving like dogs, which sparks Dave's suspicions about the company he is defending. When his dog-like behavior annoys the judge, Dave is removed from the case. He then decides to take matters into his own hands and infiltrates Grant and Strictland headquarters while in his canine form.
Hidden in the laboratory, Dave witnesses Dr. Kozak injecting the ailing Strictland with a drug that will paralyze him for several months, giving Kozak enough time to usurp control of the company. After viewing security cameras, Kozak and his minions realize that somehow Dave Douglas was able to become the exact copy of Khyi-yag-po.
When Dave comes home, still in his canine form, he overhears a conversation between Carly and Josh that Dave and Rebecca are splitting up. After hearing this Dave then knocks over a Scrabble and then used the letters to spell "I AM DAD" to his children, then spells "GRAND AND STRICTLAND" to them, making them realize the truth. Unfortunately when Dave gets out of the house he is then captured by Kozak's minions.
After the humans leave, Dave and all the other mutants plan to escape. Acting on Khi-yag-po's advice, Dave calms himself, then in human form breaks open his cage and opens the others. They all pile into a car and drive to the courthouse, but get into traffic making Dave leaving animals to drive (which then was droved near the courthouse making a scene after Dave said "I don't know how that car get here!") while he mets his wife and children in his canine form. When Dave said "I love you" he then turns into his human form.
In the court room, Dave attempts to show the assembly what Kozak has done, but only succeeds in doing so when he tricks Kozak into growing a tail. Grant and Strictland Corporation is thrown into disgrace, and Dave is able to spend more time with his family, though some of his canine habits remain. Hidden in the credits is a scene showing Kozak escaping from jail, to presumably return in a sequel.
- Tim Allen as Dave Douglas
- Robert Downey Jr. as Dr. Kozak
- Kristin Davis as Rebecca Douglas
- Danny Glover as Ken Hollister
- Philip Baker Hall as Dr. Lance Strictland
- Zena Grey as Carly Douglas
- Spencer Breslin as Josh Douglas
- Bess Wohl as Gwen Lichtman
- Jarrad Paul as Larry
- Jane Curtin as Judge Claire Whittaker
- Shawn Pyfrom as Trey
- Cole as the Shaggy Dog
- Jane Hajduk as News Reporter
- The film opened at the theaters with about $16 million. When it ended its run at the box office, the film made a domestic gross of $61,123,569 and a foreign gross of $26,010,711 adding to a worldwide gross of $87,134,280.
- In the Netherlands, the film debuted at #5 in the Boxoffice Top 10, grossing € 169.982 in that week.
Many reviews from critics were negative. BBC called Allen uninteresting and "only stops short of leg-humping in his attempts to win our affections" The film was on Richard Roeper's Worst films of 2006 list. Roger Ebert did not enjoy the film either. The movie was nominated for three Razzies, one for Worst Actor, Worst Remake, and "Worst Excuse for Family Entertainment". However, the San Francisco Chronicle liked it, calling it "as good as family entertainment gets" and Reel.com called it "the best of the recent slew of Disney remakes". It is also a popular cult film among teens and is the source of many slang phrases, such as byark, kozak, and foine. The film has a 27% "Rotten" rating on Rotten Tomatoes with 103 reviews with a rating of 4.4/10.
- Tim Allen says the line, "To infinity and beyond!" in this film, making a reference to Buzz Lightyear, whose voice Allen provided in the Toy Story films also distributed by Disney.
- Before and after the movie, the Walt Disney Pictures logo becomes a doghouse.
- This is also the final time that the 1985 Walt Disney Pictures logo is used before a movie. Starting with Pirates of the Caribbean: Dead Man's Chest, the current Walt Disney Pictures logo is used.
- Actor Jared Paul, who played Brad's friend Jason in the TV series Home Improvement (in which Tim Allen also stars), makes an appearance in the film as Larry, one of the scientists.
- The son of Tim Allen's character was listening to the song "Greased Lightning", a song that was performed on Tim's TV show Home Improvement. The song title was later parodied by Disney in a season 1 episode of Phineas and Ferb, "Greece Lightning".
- The end credits song, "Big Dog", is written and produced by famous artist-songwriter Akon.
- This film marks the first time Alan Menken composed a music score for a Disney live-action film.