Bcl-2 family members are important regulators of cell survival and cell death. Researchers have focused mainly on mitochondria, where both proapoptotic and antiapoptotic family members function to regulate the release of cytochrome c and other mediators of apoptosis. However, as reviewed here, Bcl-2 family members also operate on another front, the endoplasmic reticulum (ER), to both positively and negatively regulate the release of Ca2+. There is abundant evidence that Ca2+ signals trigger apoptosis in response to a wide variety of agents and conditions. Conversely, Ca2+ signals can also mediate cell survival. Recent findings indicate that Bcl-2 interacts with inositol 1,4,5-trisphosphate (IP3) receptor Ca2+ channels on the ER, regulating their opening in response to IP3- and thus inhibiting IP3-mediated Ca2+ signals that induce apoptosis while enhancing Ca2+ signals that support cell survival.