Loading of classical major histocompatibility complex (MHC) class II molecules with antigen-derived peptides is fast, efficient and highly selective in vivo, quite in contrast to in vitro findings with isolated class II proteins and synthetic peptides. Do accessory proteins speed up the loading process in antigen-presenting cells? Here, a model is presented in which the nonclassical MHC class II molecule HLA-DM plays a pivotal role as a chaperone, catalyst and editor during epitope selection.