CD4+ T cells (TCD4+) are activated by peptides, generally 13-17 amino acids in length, presented at the cell surface in combination with highly polymorphic MHC class II molecules. According to the classical model, these peptides are generated by endosomal digestion of internalized antigen and loaded onto MHC class II molecules in the late endosome. Historically, this “exogenous” pathway has been defined through the extensive use of purified proteins. However, the relatively recent use of clinically relevant antigens, those of influenza virus in our case, has revealed several additional pathways of peptide production, including some that are truly “endogenous”, entailing synthesis of the protein within the infected cell. Indeed, some peptides appear to be created only via endogenous processing. The cell biology that underlies these alternative pathways remains poorly understood as do their relative contributions to defence against infectious agents and cancer, and the triggering of autoimmune diseases.