The long-term objective of our research is to understand the molecular mechanism by which immune T lymphocytes recognize antigen through self restriction. It appears that recognition systems for foreign antigens have evolved from self-recognition mechanisms and that highly polymorphic self markers, the histocompatibility antigens are central to this process. For some years we have been studying the structure of human histocompatibility (HLA antigens and a complete amino acid sequence for one antigen has been recently completed. We are now at a point where comparative studies to answer the many questions raised by the functionally important, serologically detected poly-morphism of these molecules can be undertaken. This goal is aided by the availability of monoclonal antibodies which provide more reliable tools for defining these questions. The problems to be investigated have emerged as a consequence of our analysis of anti-HLA-A,B,C monoclonal antibodies.