The major histocompatibility complex (HLA system in Man) is characterized by its extensive degree of allelic polymorphism. After the serological and cellular methods, the molecular biological methods appeared to be a powerful tool in detecting HLA-class II polymorphism. Restriction fragment length polymorphism (RFLP), using restriction endonucleases, represented an efficient method of HLA-DR, DQ, and DP genotyping. Recently, the polymerase chain reaction (PCR) permitted the development of two major class II genotyping techniques: the PCR allele specific oligonucleotide typing and the PCR-RFLP typing. By these new methods, a refined and accurate determination of DRB, DQB, DQA, and DPB alleles is possible. The major application of a refined HLA class II typing is in transplantation especially for unrelated bone marrow grafts. Moreover, it permits the identification of the amino acids implicated in the cellular response which by itself is important for the fundamental immunological studies.