When Karen's has trouble dealing with a personal tragedy, Will, Grace, and Jack try to intervene. Will and Grace's new business relationship begins to show signs of stress.

Grace brings Will for support when she goes home to celebrate her deceased mother's birthday. Jack's faith in love is crushed after breaking up with Drew and uncovering a secret in Karen's marriage.

Grace's father and Will's mother end up making a surprising and upsetting connection. Jack rebounds from his breakup with a new love. Karen must decide between her husband and her lover.

Will, Grace and Jack are upset when they discover they’ve been too preoccupied with the changes in their own lives: Will teaching law at Columbia, Grace running for president of the New York Interior Designers Society and Jack’s new relationship with Estefan to even notice Karen has not been seen in days – ever since her husband found out about her affair with Malcolm.

Jack and Estefan's wedding takes a detour when they're forced to get married at the airport by their friend Miss Coco. Will's worried his relationship may turn long-distance. Grace meets a charming guy. Karen reconsiders her commitment to Nikki.

Despite her history of transgressions, Grace and her neighbor, James, decide to give their relationship one more shot. But when James invites Grace to his job at the aquarium, she endangers his job and a species. In order to help Will deal with his anxiety about becoming a father, Jack takes him to an unexpected place to blow off steam – church. Karen finds herself in a confessional booth, and a visit from Smitty makes her reconsider their entire relationship.