The endoplasmic reticulum (ER) is the main site for protein folding, lipid biosynthesis, and calcium storage in the cell. Disturbances of these critical cellular functions lead to ER stress. The ER responds to disturbances in its homeostasis by launching an adaptive signal transduction pathway, known as the unfolded protein response (UPR). The UPR strives to maintain ER function during stress; however, if the stress is not resolved, apoptotic responses are activated that involve cross talk between the ER and mitochondria. In addition, ER stress is also known to induce autophagy to counteract XBP-1-mediated ER expansion and assist in the degradation of unfolded proteins. One family of proteins involved in the regulation of apoptosis is that of B-cell lymphoma protein 2 (Bcl-2). Complex interactions among the three subgroups within the Bcl-2 family [the antiapoptotic, the multidomain proapoptotic, and the Bcl-2 homology domain 3 (BH3)-only members] control the signaling events of apoptosis upstream of mitochondrial outer membrane permeabilization. These proteins were found to have diverse subcellular locations to aid in the response to varied intrinsic and extrinsic stimuli. Of recent interest is the presence of the Bcl-2 family at the ER. Here, we review the involvement of proteins from each of the three Bcl-2 family subgroups in the maintenance of ER homeostasis and their participation in ER stress signal transduction pathways.