MHC class II alleles play a major role in determining resistance or susceptibility to autoimmune disease. Considerable effort is being expended to establish the role polymorphisms play in influencing the binding of antigens, including autoantigens, in the peptide-binding groove. Single amino acid substitutions in the MHC cleft, for instance at DR beta 71 and DQ beta 57, influence peptide binding. Although candidate autoantigenic peptides have been identified which bind to disease-associated MHC molecules, several critical questions remain to be answered before the role of these peptides in the autoimmune disease process can be established.