The major histocompatibility complex (MHC) loci are amongst the most polymorphic regions in the genomes of vertebrates. In the human population, thousands of MHC gene variants (alleles) exist that translate into distinct allotypes equipped with overlapping but unique peptide binding profiles. Understanding the differential structural and dynamic properties of MHC alleles and their interaction with critical regulators of peptide exchange bears the potential for more personalized strategies of immune modulation in the context of HLA-associated diseases.