The association of HLA-B27 with ankylosing spondylitis (AS), first described more than 20 years ago, triggered intensive research all over the world. AS is a disease model to study the interplay between genetic, immunologic, and environmental factors in the induction of rheumatic disease. Over the past years, substantial advances have taken place in the area of the molecular and cellular immunology of the HLA-B27 molecule, HLA-B27 subtype polymorphism, peptide binding and presentation to cytotoxic T cells, and their relevance to disease. New insights into the pathogenesis of the spondylarthropathies come from the development of animal models, namely HLA-B27/human beta 2-microglobulin transgenic rats, and HLA-B27 transgenic, beta 2-microglobulin knock-out mice. The role of gram-negative bacteria and gut inflammation in the development of ankylosing spondylitis continues to be the focus of interest in many studies. In this review, recent hypotheses of the pathogenesis of AS and its relationship to HLA-B27 are discussed.