Insulin dependent diabetes mellitus (IDDM) is closely associated with special MHC gene products. The class II gene products, HLA-DR3 and DR4, may be the primary susceptibility genes for IDDM. They mediate the pathogenetical immune mechanisms which, under the additional influence of special MHC-genes of class I and III, lead to diabetes. The extremely high frequency of HLA-DR3, DR4 heterozygotes among diabetic patients and the genetic heterogeneity in B8, DR3 positive patients on the one hand and B15, DR4 positive diabetics on the other with regard to various clinical, epidemiological and immunological parameters, point to the existence of at least two different diabetes susceptibility genes. They act synergistically when they occur together. Thus simple genetic models (autosomal dominant, autosomal recessive, gene dosage) do not appear to be relevant here. The increased diabetic risk for the identical siblings of DR3, DR4-positive patients offers a good opportunity of studying genetically influenced immune deviations in the prediabetic phase which result in the suppression and destruction of Beta cells and finally in the manifestation of diabetes.