This chapter reviews the genetics of Kleine-Levin syndrome (KLS) and menstrual-related hypersomnia (MRH). Up to now, two cases of monozygotic twins affected with KLS have been published. In the first case, the first-born twin showed a less typical form, in which there was no compulsive eating, but instead decreased eating. In the second case there was not such a difference as neither of the twins showed compulsive eating. Based on the recurrence of hypersomniac episodes, the frequent infectious precipitating factors at onset, the generally young age at onset and a marginally significant association with HLADQB1, an autoimmune etiology has been suggested. The autoimmune hypothesis, suggested by an initial human leukocyte antigen (HLA) association, does not seem to be replicated in larger population. Nevertheless, potential association between KLS and other autoimmune disorders might help a better understanding of implication of immune-related processes in the pathophysiology of KLS.