The film tells the story of the Irish-Catholic Fitzpatrick Brothers, Mickey (Burns) and Francis (McGlone) and the trials and tribulations of love, betrayal, and family. Mickey is a New York City cab driver, unhappy over an act of infidelity by Heather (Diaz), his ex-fiance, and Francis is a Wall Street stock investor, unhappy over his own infidelity to Renee (Aniston), his wife.
While driving his cab Mickey picks up Hope (Maxine Bahns), a girl with whom he becomes infatuated and impulsively marries that same week. This causes consternation in his brother, not with the speed of the marriage but because he was not the best man at the wedding. Mickey moves in with Hope and becomes disillusioned over her bohemian lifestyle which includes living in a ramshackle apartment where the electricity is frequently out, her blue-collar waitressing job, and shopping at discount stores.
Francis, however, is also having problems in his marriage. He is concerned that he is being unfair to Heather, his mistress, the very same woman Mickey left, by continuing to stay with his wife. Her family suggests that he may be gay, and she has Mickey and their father Frank confront him about it. He insists to his family that he is not gay but admits to being unfaithful.
Meanwhile, Francis' arrogance leads him to take potshots at his brother for the apparent lack of forward progression in his life with his wife, while Francis argues with Heather about her own sexual infidelity with a much older man referred to as "Papa".
One day, Mickey picks up Heather in his cab and agrees to go up to her apartment. However, even though Heather comes on mildly to Mickey, he does not reciprocate and, instead, takes back the television set he had given her. This upsets Heather and she demands Mickey's watch (a gift she had bought him) in return. He surrenders it to her gladly.
Throughout all this is a subplot involving Frank's own marriage. He commiserates regularly with his sons over their mother's constant presence in church, which he believes is because of the unconventional lives their sons are living, leading her to be out of the house frequently to pray for her sons. However, Frank learns during a fishing trip with the church's pastor, Father John, that his wife hasn't been to Mass in months.
On a visit to Heather's place Francis notes that the television is missing and Heather tells him where it went. Francis makes an unexpected visit to his brother's apartment and questions Mickey about his visit with Heather. They get into an argument over whether or not Mickey had sex with Heather. Later, Mickey sees Francis wearing the watch that he gave back to Heather and he finds out that the woman that Francis is seeing is none other than Heather. The revelation escalates to an argument in their parents' home during a birthday dinner for their father. In an attempt to settle the dispute, Frank takes both Francis and Mickey outside and ties boxing gloves on each, with the intent of having them fight out their differences. Mickey drops Francis in one punch.
Eventually, Francis confronts Renee and files for divorce in order to marry Heather. When Mickey finds out about the impending marriage, he informs Francis that Heather was once a prostitute. This causes Francis to get cold feet and angers Heather. She tells Mickey that she thought that he didn't have a problem with her prior choice of employment, and Mickey says that he still doesn't have a problem with it, but Francis may, and that he has a right to know.
Then, Hope drops the bomb on Mickey. She is moving to Paris. While trying to figure out what to do, he comes to Hope's place of employment and talks with Connie (Leslie Mann), one of Hope's coworkers. Mickey's talk with Connie leads him to decide to move to Paris with Hope.
Due to Francis' indecision over marriage in light of the news that Heather was a prostitute, Heather marries Papa instead. When Francis threatens Heather with telling Papa that Heather was a prostitute, Heather tells Francis that Papa was "her best customer". He then calls Renee in hopes of getting back together with her but she is already in another relationship with Scott Sherman, an overweight computer technician and mutual acquaintance whom Francis had made fun of in an earlier scene.
At the end, Mickey and Francis, along with their father and Hope, go fishing on his father's boat. Francis, the Wall Street investor with everything, now has switched places with Mickey, the man with "no real job". The trials of Heather and Renee have humbled Francis, and Hope helped pull Mickey out of his rut. The movie ends with Hope asking to drive the boat, but Frank says they haven't come that far yet in their dealings with women.