Cytotoxic, or helper T cells recognize antigen via T cell receptors (TCRs) that can see their target antigen as short sequences of peptides bound to the groove of proteins of major histocompatibility complex (MHC) class I, and class II respectively. For MHC class II epitope selection from exogenous pathogens or self-antigens, participation of several accessory proteins, molecular chaperons, processing enzymes within multiple vesicular compartments is necessary. A major contributing factor is the MHC class II structure itself that uniquely offers a dynamic and flexible groove essential for epitope selection. In this review, I have taken a historical perspective focusing on the flexibility of the MHC II molecules as the driving force in determinant selection and interactions with the accessory molecules in antigen processing, HLA-DM and HLA-DO.