It is now clear that peptides play a key role in stabilizing the structure of MHC class II molecules. Here, Scheherazade Sadegh-Nasseri and Ron Germain propose that newly synthesized MHC class II, and indeed class I, molecules behave like partially folded proteins, with peptides acting as a surrogate portion of the MHC polypeptide structure that is necessary for completion of conformational maturation.