Ever since a childhood birthday party where a hex was placed upon him, Chuck (Dane Cook) has been cursed with bad luck with women. As an adult, Chuck is not aware of the curse, but it nonetheless results in difficulties in relationships and has resulted in a fear of commitment on his part. While at a wedding of an ex-girlfriend, Chuck bumps into Cam Waxler (Jessica Alba), an attractive yet incredibly clumsy woman. They meet again after Cam slips and falls at her job, chipping a tooth, which Chuck (a dentist) graciously repairs for her. Despite the desire of both to avoid a relationship, the two eventually date. However, after investigating Chuck's past girlfriends, a friend of his hits upon the true nature of his curse: Every woman with whom he becomes intimate eventually breaks up with him and falls madly in love with the very next man she dates. After learning of this, Chuck is sent into a panic, fearful that he will lose Cam, yet willing to do anything to save the relationship.