Major histocompatibility complex class I (MHC I) proteins help protect jawed vertebrates from intracellular pathogens and cancer. This protection is achieved by MHC I proteins binding peptides and presenting them to receptors on the surface of T cells or Natural Killer cells. Recognition of peptide-MHC complexes by these receptors can activate the cytotoxic cells, leading to the elimination of the cells on which the peptide-MHC complexes are expressed. Which peptides are presented by MHC I proteins is therefore a key determinant of successful immune responses. Peptide selection occurs in the endoplasmic reticulum, where MHC I proteins sample peptides transported from the cytoplasm by TAP, the transporter associated with antigen processing. The initial loading of MHC I proteins occurs with low selectivity, with most peptides available for selection likely to be ill-suited for the peptide binding specificities of the highly polymorphic MHC I molecules that are expressed. However, the binding of low affinity peptides prevents empty MHC I molecules from aggregation. The peptides are then iteratively exchanged until MHC I proteins are loaded with peptides closely matching their peptide binding specificities. This process first occurs in the ER, where tapasin facilitates iterative peptide exchange and links newly assembled MHC I:beta2-microglobulin heterodimers to the TAP transporter, and recruits ERp57 and calreticulin to form peptide loading complexes. Subsequently, the tapasin-related protein, TAPBPR, co-ordinates with UDP-glucose:glycoprotein glucosyltransferase and calreticulin to return MHC I complexes that are loaded with low affinity binding peptides from the cis-Golgi to the ER, providing a second peptide editing opportunity. Once loaded with a high affinity binding peptide, MHC I molecules reach the cell surface where they perform their peptide presenting function.