The discovery of the structure of deoxyribonucleic acid (DNA) by Watson and Cricks in 1953 marked a time for subsequent breakthroughts in our understanding of disease. For example, the cause for a common hereditary hemoglobin defect namely, sickle cell anemia, was found to reside in a point mutation in a critical DNA sequence coding for glutamic instead of valine. This review focus on the contribution of molecular biology in unraveling the genetic basis for susceptibility to autoimmune disorders. By means of recent technical developments in this field it has been possible to establish the structure of molecules of known influence in both regulating the immune response and predisposing to autoimmunity. For examples, genes coding for class II molecules have been cloned and sequencies obtained to probe genomic DNA in the for susceptibility patterns. In this regard, the Southern blot technique has become a powerful ancillary tool to HLA typing in studying gen/disease associations. Furthermore, refinements in techniques allowing the sequencing of relevant DNA segments have made possible to obtain data strongly sugesting that relatively short nucleotide sequencies rather than broad specificities are probably responsible for conditioning an autoimmune response. The possibility of such sequencies copying into genes from diverse haplotypes by the gen conversion mechanism may explain the failure in establishing as yet a perfect HLA class II/autoimmune disease association. Also, the definition to a very high resolution of the bidimensional structure of the antigen combining site is rapidly leading to important clues regarding the role of environmental agents in triggering autoimmune responses. Such is the case of a shared sequence in the capside of Epstein Barr virus and the third hypervariable region of the class II molecule present in the HLA-DR4 specificity, the one linked to susceptibility to rheumatoid arthritis. Such exciting new concepts as well as recent data from immunogenetic studies in the most common autoimmune disorders form the basis of this review.