Advances in immunogenetics and histocompatibility have facilitated the clinical transplantation of solid organs and tissues. Improved definition of HLA antigens, alleles, and haplotypes has clarified the diversity of the HLA system among different racial/ethnic populations. Knowledge of allele and haplotypes frequencies derived from these studies can be applied to the estimates of transplant compatibility and the likelihood finding suitable donors. Humoral sensitization that has been a major barrier to transplantation is being successfully treated with desensitization and paired donor exchanges. Sensitive solid phase immunoassays for HLA-specific antibodies permit analyses that guide both desensitization and donor exchanges through antibody monitoring, virtual crossmatches, and detection of cryptic sensitization. Ongoing studies are investigating the mechanisms underlying the down-regulation of donor HLA-specific antibodies.