Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology. Pathologically, RA is characterized by a destructive synovitis in multiple diarthrodial joints and immunologically by the presence in serum and joint fluid of autoantibodies to IgG (rheumatoid factor). The diagnosis remains a clinical one and, as such, RA investigations use epidemiologic methodologies. It is now clear that there is an important genetic contribution to the etiology of RA evidenced by the association of the disease with HLA-DR4, an allele of the major histocompatibility complex located on the short arm of chromosome six. HLA associations with RA occur in several different populations. This genetic epidemiologic approach substantiates the HLA association with disease and lays the foundation for recent molecular genetic discoveries that are reviewed, particularly the MHC structure and function.