HLA antigens are the major barrier to successful transplantation. Three of the seven heterodimers (HLA-A, -B, and -DR) contribute most to the immunogenicity of a mismatched organ. Although classical serology has been used in the past to phenotype donors and recipients, histocompatibility laboratories are increasingly turning to DNA-based methods to directly genotype patients and donors for the alleles of the HLA complex. Some methods are still evolving, while several others are established well enough to use in the clinical laboratory. The application to solid organ transplantation will result in greater accuracy and a better correlation between HLA matching and graft survival in the future. In fields such as bone marrow transplantation, where matching is critically important for prevention of graft-versus-host disease and engraftment, molecular HLA testing is already being mandated by the transplantation community.