Ryan Bingham (GEORGE CLOONEY) is a man who's hired by other companies to fire their employees when he's not delivering motivational presentations about the pitfalls of being weighed down by literal and metaphorical distractions. He's quite good at what he does, and actually seems to enjoy being on the road for nearly the entire year. That's especially true since that gives him all sorts of perks that will only increase now that he's soon going to join an elite and small group of people who've racked up ten million frequent flier miles.
A committed bachelor who views airports, planes and hotels as his "home" and hasn't kept in touch with his sisters, Kara (AMY MORTON) and Julie (MELANIE LYNSKEY), he also likes being able to hook up with fellow work travelers such as Alex Goran (VERA FARMIGA) who, like him, isn't looking for anything more than a good time at a nice hotel when their paths cross somewhere across the country.
Accordingly, he isn't pleased when young upstart Natalie Keener (ANNA KENDRICK) convinces their boss, Craig Gregory (JASON BATEMAN), that their company could be more efficient and cost-effective if they'd fire others' employees virtually rather than in person. Realizing his lifestyle and accumulation of travel miles is now at risk, Ryan proves that such termination requires a direct, personal touch. But that backfires on him when Craig orders that Ryan have Natalie accompany him across the country to learn how that's done in person.
As Ryan begrudgingly shows her the ropes, he also finds his belief system challenged, not only by Julie's pending marriage to Jim Miller (DANNY McBRIDE), but also due to the fact that he's starting to fall for Alex.