The HLA system is comprised of more than 30 class I and class II genes that encode a polymorphic array of cell-surface glycoprotein molecules that function to restrict or direct the specificity of T-cell responses. Class I alloantigens, encoded by HLA-A, -B, and -C genes, historically have been identified and characterized by the use of alloantisera. Three additional class I genes, HLA-E, -F, and -G, have been identified recently, but it is not known yet if these are relevant to transplantation. The demonstration of further polymorphism among class I alleles, however, has been made possible by the use of cytotoxic lymphocytes and by isoelectric focusing gel electrophoresis. Class II alloantigens, encoded by DR, DQ, and DP genes residing in the HLA-D region, can be defined both serologically and by the use of cellular reagents. Recent advances in DNA typing methods, including restriction fragment length polymorphism and sequence-specific oligonucleotide probe analysis, provide tools which more completely define the extent of HLA polymorphism within given populations. The diversity of allelic variation within the HLA system, coupled with the fundamental role of class I and class II molecules in the triggering of allograft reactions, necessitates the continuing improvement of techniques for characterizing distinct HLA molecules and providing for the better matching of donor and recipient prior to allotransplantation.