Background When unfolded proteins accumulate in the endoplasmic reticulum (ER), they cause ER stress and activate the pathways of unfolded protein response (UPR), constituted by a set of canonical ER stress transducing proteins. While the classical UPR is well-studied, the functions of non-canonical ER stress transducers are emerging. Findings The CREB3 (cyclic AMP responsive element binding protein 3) family, which contains five members including CREB3, CREB3L1, CREB3L2, CREB3L3, and CREB3L4, is the most important non-canonical ER stress response factor sensing and modulating unfolded protein homeostasis. As novel ER stress transducers, the CREB3 family plays important roles in regulating protein folding, modification, and secretion, contributing to biological events, including cell proliferation, differentiation, and migration in diverse contexts, especially in cancer. Conclusion This review summarized the roles of the CREB3 family in development and disease progression, with an aim to provide references for further research and clinical translation.