High-strung architect Peter Highman (Robert Downey Jr.) is flying home to Los Angeles for the birth of his first child. Due to some Apatow-esque farcical events (which all seem to stem from child-like aspiring actor Ethan Tremblay (Zack Galifianakis), Peter ends up being shot by an air marshal and put on a no-fly list. As luck would have it, rescue comes in the form of Tremblay, who offers Peter a lift to LA, as Ethan himself is travelling to Hollywood to try his luck at becoming a "real actor".
Straight away the two men's diametrically opposed personalities clash, and we discover that Ethan has a second motive for his travels: to scatter his recently deceased father's ashes. It is clear instantly that Highman has no patience for Tremblay, and this is not helped by the fact that Ethan decides to make a pitstop at the home of the nearest pot dealer, whom Tremblay "found on craigslist - she's very legitimate".
The situation only deteriorates when the pair discover that they have $60 left, and to add insult to injury, Ethan spent $200 on weed. Peter decides to have money wired through to Ethan's account (his wallet, along with the rest of his luggage, were left on the plane), however when they set up the transaction, Ethan uses his stage name (Tremblay), yet only has ID showing his real surname, Chase. When the obnoxious cashier (Danny McBride), who just happens to be a "handi-capable", wheel-chair-ridden vet, decides to take matters into his own hands, and attacks Peter with what looks like a police truncheon, the situation spins out of control.
When Ethan's attempts to prove himself a "real actor" by enacting scenes on request from Peter, end up exposing a more sensitive, human side to him, Peter appears to warm to Ethan. This doesn't last long, however, as Ethan's method of getting to sleep (masturbation) reminds Peter why he was so irritated by him in the first place. In the morning, as Ethan gets out of the car at a service station, Peter dumps Ethan's luggage and his pet dog Sonny out into the street before taking off in his car. To his dismay, he discovers Ethan's father's ashes in the car, and after wrestling with his conscience, decides to go back for Ethan, whom he convinces he simply went off to get them breakfast.
The pair get back on the road again, but as soon as they seem to be getting back on track, Ethan, clearly sleep-deprived, falls asleep at the wheel, causing the car to career off a flyover, making it a write-off, and giving Peter a broken arm and some cracked ribs. Peter, clearly at the end of his tether, decides to ask for his friend Darryl (Jamie Foxx) to take him the rest of the way. Peter snaps at Ethan, telling him to abandon his dreams of becoming a Hollywood star, telling him he despises him, and spitting on Sonny. After some advice from Darryl, Peter decides to seek retribution for his outburst, and offers Ethan a lift too.
Darryl takes the pair to his own house, where the conversation leads Ethan to accuse Darryl of having an affair with Peter's wife Sarah (Michelle Monaghan), before Darryl reveals that the "coffee" they are drinking was from the coffee pot Ethan was carrying, which actually contained his father's ashes. Ethan breaks down in tears at the implications of this, to be consoled by Peter. Ethan's accusations are forgotten momentarily, however the seed is now planted, and Peter phones his wife and leaves a message asking her if she has anything to tell him.
The pair get back on the road once again, and Ethan starts smoking weed. Peter, who had fallen asleep, wakes to find that, due to Ethan having locked the windows and doors, he too is stoned, as is the dog. This leads to a dreamlike sequence wherein Ethan appears to Peter as a massive hound. Through their shared intoxication, the pair have a heart to heart and Peter apologizes for his previous "derogatory statements" toward Ethan.
The pair get distracted and end up getting stuck in the queue for the border crossing into Mexico. Because Peter is clearly not an experienced cannabis smoker, his erratic behaviour causes the border official (Paul Renteria) to become suspicious of them, despite Ethan's attempts to deceive the official into thinking his glazed eyes are caused by glaucoma. The border officer orders Ethan to cut the engine and hand over the keys to the car. As the official goes to confer with his colleague, Ethan calmly takes the pot of ashes and Sonny, and walks away from the car, leaving Peter to be interrogated by the official and his colleague (Marco Rodriguez) and told, "You attempted to transport drugs across a national border. Dude, that's some serious shit."
In a further twist, Ethan shows up and rescues Peter in a daring escape involving a police chase and several counts of criminal damage, nicely summed up by Peter: "How many laws did we just break?" To repay Ethan for his daring rescue, Peter drives to the Grand Canyon so that Ethan can scatter the ashes. To reflect the poignant mood, Peter decides to confess to his earlier abandonment of Ethan, and Ethan reciprocates by telling Peter that he had his wallet all along, essentially meaning that all the preceding events were unnecessary: He had kept it in order to compel Peter into accompanying him. After initially being furious at this, Peter decides to prioritise, and at long last the companions arrive at the hospital just in time to see the birth of Rosie Highman. Due to blood loss, Peter collapses, and comes round to find that Ethan cut the umbilical cord.
The film ends with Peter, wife, and baby watching an episode of the Charlie Sheen comedy series "Two and a Half Men", with a guest appearance by -- guess who -- Ethan Tremblay! (the show having been Ethan's reason for becoming an actor).