Regulated intramembrane proteolysis (RIP) of the transmembrane transcription factor ATF6 represents a key step in effecting adaptive response to the presence of unfolded or malfolded protein in the endoplasmic reticulum. Recent studies have highlighted new ATF6-related transmembrane transcription factors. It is likely that current models for ER stress signaling are incomplete and that the expansion of the bZIP transmembrane family reflects selectivity in many aspects of these responses, including the type and duration of any particular stress, the cell type in which it occurs, and the integration with other aspects of cell-type-specific organization or additional intrinsic pathways, and the integration and communication between these pathways, not only in a cell-type-specific manner, but also between different tissues and organs. This review summarizes current information on the bZIP-transmembrane proteins and discusses outstanding questions on the elucidation of the stress signals, the repertoire of components involved in regulating different aspects of the forward transport, cleavage, nuclear import, transcriptional activity, and turnover of each of these factors, and dissection of the integration of the various outputs into broad coordinated responses.