Interest in the complexity of the HLA system and its relevance in the selection of unrelated bone marrow donors has had an important impact on our understanding of the immunogenetics of HLA and non-HLA or minor histocompatibility systems. More than 50 genes on the short arm of chromosome 6, which carries the information for HLA, have been identified and there are more to come. HLA-class I and HLA-class II each have more than 200 alleles, and the number is growing. The HLA-C antigens appear to act as targets for natural killer cells. New inroads have been made in the recognition of the minor histocompatibility antigens HA-1 to -5, which can be recognized by cytotoxic T-cell clones and are inherited in a Mendelian fashion. A mismatch for HA-1 might lead to graft-versus-host disease. The introduction of new technologies, especially polymerase chain reaction, has been immensely helpful in mapping the genetic complexity of HLA. Methodology now allows typing for HLA on the level of DNA in a matter of a few hours and is most useful when selecting a suitable bone marrow donor. The new genetic information available makes it clear that many so-called HLA matched unrelated bone marrow transplants performed in the past were actually mismatched. Nevertheless, many of them had a good clinical outcome. It is clear that one of the most important challenges is to determine which mismatched transplants will fare well and which should be avoided. Recent findings in organ transplantation might be helpful here.