ABSTRACT Class I molecules of the major histocompatibility complex (MHC) have been studied primarily for their role in presenting peptide antigens to conventional T lymphocytes. An increasing body of evidence suggests that MHC and newly characterized MHC‐related molecules have a much more varied function in the body. Many of these molecules are involved in pleiotropic interactions with other proteins, which initiate signal transduction cascades and contribute to cellular and tissue homeostasis.—Ojcius, D. M., Delarbre, C., Kourilsky, P., Gachelin, G. MHC and MHC‐related proteins as pleiotropic signal molecules. FASEB J. 16, 202–206 (2001)