Most HLA-B27 positive individuals live without noticing the risk factor they carry. Only when certain bacteria come into play, usually in the form of intestinal or genital infection, some of the HLA-B27 positive individuals will develop a reactive disease. Such an association is so well established that it has formed a basis to study the relation of autoimmune reactions to microbial infections. Early epidemiological investigations have been followed by studies on immunological cross-reactivity and recently by studies on presentation of bacterial peptides by the HLA-B27 molecule. This introductory review briefly summarizes the evolution of the research, the goal of which still remains to clarify the etiopathogenetic mechanisms of HLA-B27 associated diseases.