It has long been known that the major histocompatibility complex (MHC) is essentially involved in genetic susceptibility to ankylosing spondylitis (AS). The HLA-B27 antigen has been accounted for 20 to 50% of the total genetic risk for this disease. However, susceptibility to AS cannot be fully explained by associations with the MHC. Recent studies including linkage analyses as well as candidate gene and, most recently, genome-wide association studies indicate significant associations of the interleukin-1 gene cluster, interleukin-23 receptor and ARTS1 genes as well as other possible loci with AS. In the murine model of proteoglycan-induced spondylitis, two susceptibility loci termed Pgis1 and Pgis2 were identified. Thus, AS is not a single-gene disease and the involvement of multiple non-MHC genes may account for the individual as well as geographical differences seen in AS.