Molecular and genetic studies of HLA class-II genes provide new insights into the basis for MHC associations with autoimmunity. Polymorphisms among class-II genes identify specific haplotypes associated with autoimmune diseases such as type-I diabetes, rheumatoid arthritis, celiac disease, and pemphigus vulgaris. In some cases, single genes within those haplotypes are themselves implicated in disease susceptibility. Interactions, both cis and trans, between candidate susceptibility genes suggest a number of possible mechanisms critical for autoimmune triggering events involving class-II molecules. Amino acid sequence comparisons between products of candidate susceptibility genes and other class-II genes pinpoint a limited number of critical sites within HLA molecules which appear to be responsible for pathogenic events.