The film tells the story of Irish-Catholic Fitzpatrick brothers, Mickey (Edward Burns) and Francis (Mike McGlone) and the tribulations of love, family and betrayal. Mickey is a New York City blue-collared taxi driver, unhappy over an act of infidelity committed by Heather (Cameron Diaz), his ex-fiancée. Francis is a white-collared Wall Street stock investor, who unknown to his wife, Renee (Jennifer Aniston), is having an affair.
During weekends, Mickey and Francis visit their parents who live on Long Island. Their mother is never seen on screen, while they have better time interacting with their father, Frank (John Mahoney), whom is a emotionally bereft conservative man as well as an old-school sexist and a bigot whom takes them out fishing on his motorboat, but refuses to let women on board due to family tradition. Frank always gives Mickey and Francis advice to live out their lives any way they can and to always go for what drives them to succeed.
While driving his cab one day, Mickey picks up Hope (Maxine Bahns), a young woman and NYU art student with whom he becomes infatuated and impulsively marries that same week despite knowing her only a few days. Mickey and Hope show up one evening at Francis and Renee's apartment to inform them of their quickie marriage. This causes consternation for his brother, largely because he was not asked to be best man at the wedding. Mickey moves in with Hope, but later becomes disillusioned with aspects of her liberal and free-spirited lifestyle, including frequent power cuts in their ramshackle apartment.
Francis 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 Renee. At the same time, Renee's family, especially her younger sister Molly (Amanda Peet) suggests the problem with Francis' lack if interest in her is that he may be gay, so she has Mickey and his father confront him about it. He denies being 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 new 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 goes up to her apartment to retrieve a television that belonged to him during their relationship. Heather responds by demanding Mickey's watch, which she purchased as a gift. Mickey relents, which she implies she wants more from him, but he does not reciprocate, instead reminds her of her affair, and her previous profession. Throughout all this, Mickey and Francis' father offers more egoistical and selfish advice to them. Then Frank learns, during a fishing trip with the church's pastor, that his supposedly highly religious wife hasn't been to Church Mass in months.
On a visit to his mistress's apartment, Francis learns that Mickey and Heather have recently met. 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 discovers that she is the woman Francis has been having an affair with. 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 proves the victor.
Eventually, Francis confronts Renee about his affair 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 during her college days. This causes Francis to get cold feet and it 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 doesn't, but Francis may, and that he has a right to know.
Meanwhile, Hope has already dropped a bomb on Mickey: she is moving to Paris very soon to attend art school and Mickey is not sure about whether or not to join her. On a visit to the bar where Hope works, Mickey has a talk with Connie (Leslie Mann), one of Hope's co-workers, who claims to have had a "special relationship" with Hope before the marriage. This troubles Mickey so much that he begins to avoid Hope. Later, Hope tells Mickey that she is unsure if he should come to Paris after all and admits to having a "semi-lesbian affair" with Connie some years back. As a result, Mickey and Hope's relationship appears to be about to break up.
Due to Francis' indecision over marriage in light of the news that Heather was a prostitute, Heather decides to leave him and marry "Papa", the wealthy older man she has been seeing concurrently while she was with Francis. When Francis threatens to tell 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, a overweight mutual acquaintance whom Francis had made fun of in an earlier scene.
In the final scenes of the film, Mickey and Francis meet with their father at his house where the distraught Frank tells them that their mother had just left him the previous day and has run off with a dry-cleaning store owner whom she has been having an affair with for several months. Unsure about everything now, Frank finally apologizes to Mickey and Francis for giving them bad advice about life and love when his own wife was cheating on him behind his back. As a result, the three men decide to go out fishing aware that despite the failure of their love lives, they will always have each other. As they prepare the motorboat to cast off, only Mickey decides it would be better if he tried to have one last talk with Hope before she leaves America. Only their father has arranged a surprise guest - Hope. The movie ends with Hope asking to drive the boat, but Frank, aware that women are not allowed on board, says it is too soon for that.