One of the most conspicuous features in the HLA fold is a prominent cusp-shaped prominence in the α2 domain of class I HLA molecules, and its tri-dimensionally equivalent β1 domain in class II HLA molecules. The cusp in both molecules involved allele-diversity regions. Similarly, shaped structures have been preserved in the entire major histocompatibility complex gene product family, irrespective of whether or not they can present antigens. Importantly, cusp regions in several HLA molecules have been found to act as ligands that perform non-antigen presentation functions. For example, ligands for natural killer cell receptors have been identified in the cusp regions of both classical and non classical (HLA-E) class I HLA molecules. Thus, the cusp region, whose peculiar tri-dimensional shape has been carefully conserved through major histocompatibility complex evolution independent of antigen presentation, is a hub for signal transduction ligands that interact with a variety of non-HLA receptors and activate important biologic functions. In class II and classical class I HLA molecules, the cusp contains allelic hypervariable region. Antigen presentation per se cannot explain HLA-disease association. The major histocompatibility complex cusp theory proposes that HLA molecules may promote diseases due to their allele-specific biologic effects independent of antigen presentation function of HLA. Therefore, the blame cannot be applied exclusively to the antigen presentation fuction of HLA molecules.