A significant event in immunology occurred in 1987 with the publication of the three dimensional structure of a class I major histocompatibility complex (MHC) product as determined by X ray crystallography. The crystal structure revealed a groove created by the first and second domains of the molecule which could be the antigen (Ag) binding site. Subsequent analyses have suggested that a similar groove exists in the class II molecule. The present view will focus on the implications of this new knowledge for understanding regional immune responses. In particular, we shall discuss how the occupation of the groove by different peptides in different tissues implies that a component of T cell recognition of MHC may be tissue specific.