Members of the CREB3 family (also known as the OASIS family) are tissue-specific proteins that each contain a transcription activation domain, a basic leucine zipper (bZIP) domain that promotes dimerization and DNA binding, and a transmembrane domain that anchors the protein to the membrane of the endoplasmic reticulum (ER) (reviewed in Asada et al. 2011, Chan et al. 2011, Kondo et al. 2011, Fox and Andrew 2015). The family includes CREB3 (LUMAN), CREB3L1 (OASIS), CREB3L2 (BBF2H7, Tisp40), CREB3L3 (CREB-H), and CREB3L4 (CREB4). Activation of the proteins occurs when they transit from the ER to the Golgi and are cleaved sequentially by the Golgi resident proteases MBTPS1 (S1P) and MBTPS2 (S2P), a process known as regulated intramembrane proteolysis that releases the cytoplasmic region of the protein containing the transcription activation domain and the bZIP domain. This protein fragment then transits from the cytosol to the nucleus where it activates transcription of target genes. CREB3L1, CREB3L2, and CREB3L3 are activated by ER stress, although the mechanisms that cause the transit of the CREB3 proteins are not fully characterized. Unlike the ATF6 factors, CREB3 proteins do not appear to interact with HSPA5 (BiP) and therefore do not appear to sense unfolded proteins by dissociation of HSPA5 when HSPA5 binds the unfolded proteins.