• ER chaperones are abundant and highly conserved proteins that display both peptide binding and chaperone activity. • Of the family of chaperones present in the mammalian ER, GRP94 and calreticulin are apparently unique in their ability to elicit CD8+ T-cell responses against components of their bound-peptide pools. • The ability of GRP94 and calreticulin to elicit CD8+ T-cell responses indicates that both proteins bind peptides suitable for assembly on to MHC class-I molecules. • The capacity to function as molecular chaperones and as peptide-bind-ing proteins capable of transferring, directly or indirectly, peptides on to class-I molecules, indicates that GRP94 and calreticulin participate in the regulation of both peptide and polypeptide traffic in the ER. • Perspectives on the regulation of and interplay between the peptide binding and chaperone activity of GRP94 and calreticulin are discussed.