Antigen presentation by class II MHC proteins (MHC-II) is a critical component of the adaptive immune response to foreign pathogens. Our understanding of how antigens are presented has been greatly enhanced by crystallographic studies of MHC-II-peptide complexes, which have shown a canonical extended conformation of peptide antigens within the peptide-binding domain of MHC-II. However, a detailed understanding of the peptide loading process, which is mediated by the accessory molecule HLA-DM (DM), remains unresolved. MHC-II proteins appear to undergo conformational changes during the peptide loading/ exchange process that have not been clearly described in a structural context. In the absence of a crystal structure for the DM-MHC-II complex, mutational studies have provided a low resolution understanding as to how these molecules interact. This review will focus on structural and biochemical studies of the MHC-II-peptide interaction, and on studies of the DM-MHC-II interaction, with an emphasis on identifying structural features important for the mechanism of DM mediated peptide catalysis.