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.
Malcolm is a regular high school kid trying to navigate his way through life despite the various obstacles thrown in his way a complete misunderstanding of girls, the constant burden of masterminding plans to get himself and his brothers into or out of trouble, and a miserable job at the Lucky Aide not to mention a severe case of teen angst.
Although Malcolm has a genius IQ, he can't seem to make sense of the opposite sex, much less his embarrassing family. Lois is the outspoken, opinionated mom, who still manages to rule the roost even though her boys are growing wise to her crafty ways. Hal, a dad who is just a bumbling, big kid at heart, often finds himself creating more chaos than his five boys combined.