Narcolepsy was first shown to be tightly associated with HLA-DR2 and DQ1 in 1983, suggesting a possible autoimmune mechanism. Early investigations failed to demonstrate this hypothesis, postulating that HLA-DR2 was only a linkage marker for another, unknown narcolepsy-causing gene. The autoimmune hypothesis is now being re-evaluated under the light of recent results. Like many other autoimmune disorders, narcolepsy usually starts during adolescence, is human leukocyte antigen (HLA)-associated, multigenic and environmentally influenced. Furthermore, HLA-association studies indicated a primary HLA-DQ effect with complex HLA class II allele interactions and a partial contribution of HLA to overall genetic susceptibility. Finally, recent result suggests that human narcolepsy is associated with the destruction of a small number of hypothalamic neurons containing the peptide hypocretins (orexins). This data is consistent with an immune destruction of hypocretin-containing cells as the most common etiology for human narcolepsy.