Type 1 diabetes mellitus (T1D) remains the most intensively studied, and thus the best paradigm, of MHC-associated diseases. Accumulating evidence suggests that MHC susceptibility for T1D is recessive, with susceptibility alleles more common than protective alleles. Updated allele-level and nucleotide sequence analysis of MHC class II T1D susceptibility markers of conserved extended haplotypes underscore the uncertainty surrounding the actual T1D MHC susceptibility locus. Recent studies have established that disease concordance in dizygotic twins is the same as that in siblings generally, for both T1D and the MHC-associated autoimmune disease gluten-sensitive enteropathy, leaving little room for a differential environmental trigger. Epigenetic mechanisms are probably involved in many MHC-associated phenomena, including autoimmunity, and appear to be the best explanation for incomplete penetrance.