Helper T cells respond to peptide antigens derived from exogenous sources presented by MHC II on antigen presenting cells. Antigens from pathogens are internalized by professional antigen presenting cells (APC) and processed for presentation. Certain epitopes are selected during processing as the final peptides for stimulation of T cells and are termed "immunodominant". Understanding how selection of immunodominant epitopes takes place has been a difficult task because of the complexity of the mechanisms governing both antigen processing and T cell recognition. In this review, we discuss our current understanding of HLA-DM function in peptide exchange and selection and its relevance to epitope immunodominance.