The strong reaction of T cells against foreign major histocompatibility complex (MHC) antigens, commonly termed "alloreactivity", is not only a nuisance for clinical organ transplantation; it also remains a puzzling question for immunologists. By making use of recent technical developments, alloreactive T cells nominally directed against a mutation in a single MHC class I molecule were found to fall into several major categories. One is recognizing peptides whose occurrence is dependent on one particular MHC allele, another is recognizing peptides supported by several MHC alleles, and a third is recognizing peptides occurring independently of MHC alleles. In a fourth category, the binding to MHC of any of a broad range of peptides appears sufficient. In addition, there are T cells for which no peptide involvement could be detected at all. Even within these categories, the heterogeneity of T cells is considerable: among 16 Kb-reactive T cells analyzed, 15 different modes of reactions were found.