Human leukocyte antigen genes associated with rheumatoid arthritis are commonly found in the unaffected population, implying that causal mechanisms of disease involve interactions between these genes and other factors. A variety of approaches-genetic, structural, and immunologic-are used to explore possible molecular interactions that may contribute to understanding the basis for this disease association. The specific relation between human leukocyte antigen-DR4 alleles and rheumatoid arthritis remains one of the strongest and most thoroughly studied examples of human leukocyte antigen risk genes among human autoimmune disorders.