Apoptosis is essential for maintenance of tissue homeostasis and its deregulation underlies many disease conditions. The BCL-2 family of proteins is a group of evolutionarily conserved regulators of cell death, comprising both anti- and pro-apoptotic members, which operate at the mitochondrial membrane to control caspase activation. Different BCL-2-related proteins are also located in multiprotein complexes at the endoplasmic reticulum (ER), which are involved in the control of diverse cellular processes, including calcium homeostasis, autophagy, the unfolded protein response and ER morphogenesis. Here, we describe the emerging concept that BCL-2-related proteins have alternative functions beyond apoptosis to control the essential functions of the cell.