Modern understanding of the genetic basis of graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (HSCT) involves knowledge of human leukocyte antigen (HLA), killer immunoglobulin-like receptors (KIR), cytokine genes, and their interactions. Insights into the immunogenetic basis of GVHD come from long-standing clinical experience in the use of myeloablative conditioning regimens and donor bone marrow as the grafting source. Under these circumstances, donor T-cell recognition of host HLA can cause GVHD. The recent elucidation of HLA class I as ligands for natural killer (NK) cell inhibitory KIR demonstrates that GVHD is the result of a complex interplay between the innate and adaptive immune responses. The extent to which T cells and NK cells contribute to clinical GVHD is a function of the host post-conditioning environment, immunosuppressive treatments, and the content of the graft source. The contribution of donor and host genetic differences in cytokine genes in modulating risks of GVHD has recently been recognized.