In ankylosing spondylitis and reactive arthritis, an interplay of microbe and major histocompatibility complex initiates a sequence of events resulting in chronic inflammation. With the use of molecular probes as direct evidence and immune response patterns as indirect evidence, a strong case has been made for a central role of local microbial antigen in reactive arthritis. Cofactors such as gender, persistent gut inflammation, and antibiotic treatment may contribute to this process. Studies of transgenic rats and of familial spondylitis implicate B27 itself as the critical host variable. The results of recent studies point to intimate B27-bacteria interrelationships. HLA-B27 and proteins from enteric bacteria are structurally related, in a manner that may affect T cell response to enteric pathogens. B27 also may directly affect host-microbe interactions by modulating the invasive potential of these bacteria into target cells. Studies are in progress to apply the predictions of these in vitro systems to the in vivo situations of these diseases. The insights of research in the spondyloarthropathies may find broad applications in the rheumatic diseases.