Three-dimensional structures of human and murine MHC class I molecules in complex with peptide antigens have begun to elucidate the mechanism of peptide binding. The MHC molecule has a highly conserved structure in which important variation occurs only in the residues lining the central polymorphic portion of the peptide binding cleft. Peptides bind in extended conformations deep within the cleft and have highly specific and conserved interactions at their amino and carboxyl termini and divergent interactions in the middle. Peptides longer than the canonical length for a given allele appear to bulge in the middle but maintain their interactions at their ends. One or more anchor residues are used by the peptide to establish tight and enduring presentation to T cells. Peptide-associated conformational differences in the MHC molecule itself may contribute to the T cell recognition process.