This chapter reviews the contribution of the human leukocyte antigen (HLA) molecule in narcolepsy in terms of genetic association, relationship to clinical characteristics, autoimmune hypothesis and molecular mechanisms. The HLA genotype has been related to sleep, even in healthy subjects. In 1983, a strong association was reported in Japanese narcolepsy patients with HLA. Narcolepsy is not limited to the core symptoms of lapsing into sleep and cataplexy, but also exhibits wide range of associated symptoms that are somatic and neuropsychiatric. Among known HLA-related diseases, the relative risk of narcolepsy is extremely high. Although, there is no direct evidence for autoimmunity, studies of environmental factors in narcolepsy have suggested that previous infectious diseases could be a trigger to develop narcolepsy. Association with the HLA complex is not limited to narcolepsy, and over 100 types of diseases are known to show significant associations with HLA.