Ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are immune-mediated inflammatory joint diseases with the potential for significant target organ damage. Genetic factors play an important role in defining disease susceptibility. Both diseases are mediated in part by TNF, since anti-TNF therapies have proved effective in both AS and RA. Despite their similarities, the genetic elements associated with the respective diseases differ, most notably in HLA associations, with AS being associated with class I HLA alleles and RA associated with class II HLA alleles. AS has a predilection for axial joints whereas RA targets peripheral joints, but the immunological basis of that distinction is unknown. Autoantibody formation is the immunological hallmark of RA, whereas AS is notable for being a "seronegative" disease. Growing knowledge of new aspects of the host immune response (such as innate immune responses and Th17 cells) is adding to new insights into shared mechanisms of pathogenesis between these two diseases.