AbstractAlthough the crystal structure of HLA‐B27 has been known for a long time, only recently have X‐ray diffraction studies of this molecule in complex with individual peptides become available. The report of three such structures involving viral epitopes that are immunodominant in HLA‐B27‐restricted T cell responses against influenza, Epstein‐Barr and HIV viruses significantly improves our perception of critical aspects of the immunological and pathogenetic roles of HLA‐B27, including (1) the molecular basis of its peptide‐binding specificity and how this is modulated by subtype polymorphism, (2) the relationship between the structural and the antigenic features of immunodominant viral epitopes, (3) the basis for long term non‐progression to AIDS of HIV‐infected HLA‐B27+ individuals, and (4) the structural features of microbial peptides influencing NK receptor engagement. Here, I discuss the implications of this and related studies for the relevance of HLA‐B27 in host defense and as a pathogenetic molecule in spondyloarthritis.See accompanying article: http://dx.doi.org/10.1002/eji.200425724