Ankylosing spondylitis (AS) is a chronic, progressive inflammatory rheumatic disease involving primarily the sacroiliac joints and the axial skeleton. The main clinical features are back pain and progressive stiffness of the spine. Oligoarthritis of the hips and shoulders, enthesopathy, and anterior uveitis are common, and involvement of the heart and lungs is rare. The current understanding of the pathogenesis of this disorder is limited. Despite the strong association between human leukocyte antigen B27 (HLA-B27) and susceptibility to AS reported over the past 30 years, the exact pathogenic role of HLA-B27 in AS and other spondyloarthropathies has yet to be determined. The authors present a review of the literature pertaining to the pathogenesis of AS over the past several decades. Ankylosing spondylitis is a polygenic disorder, with HLA-B27 playing a critical causative role in its pathogenesis. Animal studies of the immunobiology of HLA-B27 have provided significant insight into the pathogenic role of HLA-B27. The search for the antigenic peptide to support the "arthritogenic peptide" hypothesis has been disappointing. Over the past decade there has been increasing interest in the critical role of the misfolding and unfolded protein response of the heavy chain HLA-B27 in the modulation of the inflammatory response. Although there have been significant new findings in the understanding of the pathogenesis of AS, the exact mechanisms have yet to be identified. There is considerable optimism that additional susceptibility genes, predisposing factors, and regulators of the inflammatory process will be identified that will provide avenues for future treatment.