Until recently it was generally assumed that the focus of T cell receptor recognition of allogeneic MHC molecules was the polymorphic regions on the molecule that differed between responder and stimulator. It is now clear that all T cell recognition, including self-tolerance and allorecognition, involves both the MHC molecule and its associated peptide ligand. Polymorphic residues located within the peptide binding groove of the MHC and inaccessible to the T cell receptor can profoundly affect selection and recognition of bound peptides. These peptide differences between histoincompatible individuals greatly amplify the antigenic impact of MHC polymorphism and result in the high frequency of alloreactive cells. Evidence for the role of peptides in allorecognition is reviewed.