It has been established that as molecular chaperones, the glucose-regulated proteins (GRPs) play an important role in maintaining cellular homeostasis. This conventional concept of GRPs as protein folding chaperones is updated by discoveries that GRPs promote tumor proliferation, metastasis, drug resistance, immunotherapy, which have major clinical implications in the prognosis and treatment of cancer. Further, the localization of GRPs on the cell surface of certain cell types suggests that they serve new functions as cell surface receptors for signaling. These and other new developments on the role of GRP78, GRP94 and GRP170 in cancer progression and therapy are discussed in this review.