Rheumatoid arthritis (RA), like other autoimmune diseases, has a complex genetic basis. Rapid technical advances in high-throughput genotyping and analysis have now reached a point where genes of low-to-moderate risk can be identified using a variety of study designs, including whole genome association studies. The availability of large, well-characterized populations of cases and controls are critical to the success of these efforts. A functional variant (R620W) of the intracellular protein tyrosine phosphatase N22 (PTPN22) has now been conclusively shown to confer approximately two-fold risk for seropositive RA as well as several other autoimmune disorders. PTPN22 appears to act primarily by setting thresholds for T-cell receptor signaling, and the current data suggest that the PTPN22 620W allele is likely to be a general risk factor for the development of humoral autoimmunity. PTPN22 is expressed widely in hematopoietic cells, but other than in T cells, its role is unknown. These results provide strong evidence for the longstanding hypothesis that common genes underlie different autoimmune phenotypes and emphasize that finding genes of only moderate risk can provide important insights into disease pathogenesis.