When Hal and Lois go out of town for a "last chance" getaway before the baby comes, Reese has a big bash that gets out of hand. College-age thugs show up, cancel the party and set up a drug-making operation in the garage. All Reese and Malcolm can do is knuckle under. The good news is, Dewey's not around. The bad news is, his baby sitter is Lois's annoying co-worker Craig. Meanwhile, Hal and his very pregnant wife are off at a romantic retreat---feuding.

Jamie's babysitter coerces Malcolm into doing a "small" task for her; Dewey finds a friend, only to lose him to Reese; Francis persuades Otto to confront an old adversary that once courted Gretchen.

Reese's new girlfriend Beth is about as dumb as he is. Malcolm initially dislikes her but they soon get to like each other too much and Beth breaks up with Reese. Devastated, Reese runs away and joins the army under the false surname.

During Grandma's unwelcome visit with the family, she loses her leg while saving Dewey from a moving truck. Consumed with guilt, Dewey is determined to find his Grandmother's leg and give it the proper burial. Francis, on the other hand, begrudgingly becomes the caretaker for his stubborn, cranky grandmother. Meanwhile, Malcolm and Reese are given a new idea for a prank that forces them to stay awake days at a time to avoid the embarrassment of having their faces glued to the floor.

When Francis and Piama choose to celebrate Francis' 21st birthday at the house, Hal is reminded of a promise he made to his son as a young child, involving a motorcycle trip that Lois quickly forbids. Hal and Francis have no choice but to sneak off for their wild adventure, leaving their women behind. Meanwhile Malcolm, Dewey and Reese are held captive in their own home by a bully.

Reese and Malcolm try to perform the ultimate Halloween prank.

Lois discovers she has mono after a visit to the doctor. She then ends up giving it to Malcolm after her maternal instincts begin. As a result, both Lois and Malcolm are forced to spend an entire day and night together in the same room. Hal, meanwhile, is invited to all of his neighbors' parties after they know Lois will not be attending any of them.