The strong association between HLA-B27 and ankylosing spondylitis has been known for more than 33 years, but the enigma of the pathogenetic role of the gene and its product has not yet been solved. Ongoing studies have produced evidence supporting different theories to explain this association, and structural and functional studies of HLA-B27 allele products at molecular level have provided information of broad and multidisciplinary value and disclosed new avenues leading to autoimmunity and immune disregulation.