Presentation of antigenic peptides by MHC class II molecules to CD4(+) T cells requires many events in both the biosynthetic and endocytic pathways that must all occur in a controlled and coordinated fashion. In recent years the roles of two important chaperones, the invariant chain and the HLA-DM dimer, in promoting the acquisition of peptides by MHC class II molecules have largely been elucidated. The different compartments within the endosomal/lysosomal pathway that are involved in peptide loading are now being characterized. In addition to the specialized MHC class II compartments that exist in antigen-presenting cells, other intracellular compartments may also be involved in peptide loading. The precise mechanisms and intracellular sites of MHC class II peptide loading appear to dictate the nature of the T-cell epitopes presented by the antigen-presenting cell.