Although the influence of HLA-B27 on the development of spondyloarthropathies is undisputed, its role in pathogenesis remains unclear. New ideas have focused on abnormal characteristics of HLA-B27 resulting from aberrant folding, disulfide bond formation, or both, rather than a predilection for selecting arthritogenic peptides. This reflects, in part, unanswered questions about whether immunologic recognition of HLA-B27 is required for disease. Recent studies suggest that CD4+ T cells, immunomodulatory killer cell Ig receptors, and Ig-like transcript receptors may recognize aberrant forms of HLA-B27. Other reports suggest that HLA-B27 expression can alter cytokine production from monocytes and T cells-effects that appear unrelated to antigen presentation. Novel bioinformatics approaches have led to the identification of HLA-B27-restricted pathogen-derived peptides and may prove useful in determining whether HLA-B27 presents arthritogenic peptides. Elucidating the role of HLA-B27 in the pathogenesis of these conditions will require an integration of information from animal models, genome-wide screens for susceptibility alleles, and translational studies using human samples.