The major genetic susceptibility to insulin dependent (Type 1) diabetes is determined by genes in the HLA chromosomal region. An increased relative risk for developing the disease is observed in subjects who are HLA A1, A2, B8, B18, B15, B40, CW3, Bfs, DW3, DW4, DRW3, DRW4 positive. There is an additive relative risk in subjects who possess two "high risk" HLA B alleles which has an important influence on the prevalence of the disease in sibships and possibly on the concordance rate in diabetic identical twins. There is also suggestive evidence that particular combinations of "high risk" HLA B alleles are associated with increased or persistent antibody production which may reflect enhanced or differential susceptibility. Certain factors (e.g. HLA B7, DW2 and DRW2) are associated with a significantly reduced risk and may exert a "protective" mechanism in Type I diabetes, by linkage disequilibrium with genes which reduce immune responsiveness. The significant increases and decreases in respect of the HLA B antigens are probably secondary to the corresponding HLA D and DRW associations which reflect a stronger linkage disequilibrium between the genes which determine these specificities and the putative genes which control susceptibility. Initial damage to the beta cells probably occurs a considerable time before the onset of symptoms and theoretically modification of the immune response early in the disease process may reduce the rate of beta cell destruction.