Five years after Knocked Up, Debbie owns a boutique, and among her employees are Jodi and an attractive woman named Desi about whom Debbie and Jodi gossip. Pete owns his own record label, but it struggles financially as he promotes the reunion of Graham Parker & The Rumour. The couple also deal with conflict between their daughters, 13-year-old Sadie and eight-year-old Charlotte. For Debbie’s 40th birthday, the couple goes on a romantic weekend to a resort. There they get high on marijuana cookies and fantasize out loud about ways they would kill each other.

After speaking with her friends Jason and Barb, Debbie decides to improve her marriage and family through exercise and strengthening her relationship with her father. She tells Pete he needs to stop lending his father Larry money because it is hurting them financially, but Pete fails to follow through with this. Meanwhile, Debbie learns she is pregnant but decides not to tell Pete. Later, she yells at a student, Joseph, who had an online argument with Sadie on Facebook leading to a confrontation between Pete and Joseph’s mother, Catherine.

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