Development of rheumatoid arthritis is influenced by genetic and environmental factors. Over the years intense interest has been focused on analysis of genetic factors contributing to pathogenesis and it appears that the major histocompatibility complex class II genes make a major contribution. Utilizing epidemiological data as well as molecular techniques, an epitope located on a number of HLA-DR molecules (class II) seems to be associated with an increased susceptibility to development of the condition. Furthermore, the disease may be more severe among individuals homozygous for the disease-associated DR types. The specific immunological mechanisms accounting for these findings are not known but are likely related to the ability of class II molecules to bind autoantigens and stimulate the appropriate T cells which can lead to joint damage. A search for additional genetic factors contributing to disease development should be high on the list of objectives and would help to further elucidate the pathogenesis of this complex disorder.