In this article, Derry Roopenian relates the traditional view of minor histocompatibility (H) loci to recent advances in understanding of the tissue rejection process and the molecular nature of minor histocompatibility antigens. He proposes that minor H loci can be subdivided by the ability of their products to stimulate different T-cell subsets and discusses the implications of this concept in terms of the origins and behavior of minor H loci and their antigens, tumor immunology and autoimmunity.