Genetic variation has been the mainstay of hematopoietic stem cell transplantation since the first transplants were attempted. A significant expansion of genetic knowledge is under way, as the draft sequence of the human genome is annotated. Hematopoietic stem cell transplantation is a field that will greatly benefit from this new knowledge, but the manner in which it is applied is daunting. Variation within key molecules related to hematopoietic stem cell transplant in combination with the current knowledge of human leukocyte antigen variation will serve to improve donor-recipient matches and clinical outcome.