The HLA-B27 molecule is one of the most fascinating in medicine. Its contribution to the aetiopathogenesis of SpA and other diseases, and its protective action in certain infections, continue to challenge our understanding of its immunobiology and physiological roles. Animal studies have helped to cast light on ways in which HLA-B27 exerts its effects. Subtle variations in structure and behaviour between B27 subtypes that are strongly associated with SpA, compared with those whose association is neutral or weak, are helping to elucidate its pathogenetic mechanisms. However, none of the current hypotheses fully explains the observed actions of HLA-B27. Consequently, attention is turning to how haplotype linkages and genetic networks involving other MHC and non-MHC genes influence the penetrance and clinical expression of B27. HLA-B27 gives an intriguing insight into the connection between heredity and disease. As well as its close links with SpA, various other associations have been reported between B27 and diseases of different organs and systems. Evidence is also accumulating that it mitigates the virulence of HIV and other viral infections. The role of HLA-B27 as an aid to diagnosis, prognosis and disease management is gradually becoming clearer.