Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are generally considered multifactorial-that is, they involve both genetic and environmental factors. Technical advances in human genetics over the past 5 years have enabled the survey of the entire human genome for disease susceptibility genes and have contributed to a greater understanding of the molecular mechanisms underlying autoimmunity. Among the genetic predisposition factors identified to date, some variants have been found to be restricted to specific ethnic groups, which might reflect migration history and the natural selection that shaped genetic variation in these populations. Other genetic factors could also have exerted different magnitudes of risk for the disease among the different populations, which might be explained by their interactions with other genetic and environmental factors. These pieces of evidence suggest that substantial heterogeneity exists in the genetics underlying autoimmunity among different ethnic populations. This Review discusses the genetic heterogeneity in autoimmunity, with a focus on rheumatoid arthritis, between Asian and European populations. In addition to the most-studied and well-characterized gene HLA-DRB1, we will also describe examples of the gene-environment interactions between PADI4 and smoking, and the gene-gene interactions between PTPN22 and FCRL3.