In the eukaryotic cell, the endoplasmic reticulum (ER) plays an important role as the site of lipid synthesis, protein folding and protein maturation. Stringent regulation of redox and calcium homeostasis is paramount, failure of which leads accumulation of unfolded and aggregating proteins resulting in a condition known as ER stress. Eukaryotic cells deal with ER stress by eliciting the unfolded protein response (UPR). This pathway splits into two streams depending on the severity and longevity of the ER stress, where the cell must make a choice for the good of the organism between survival and programmed cell death. The BCL-2 family of proteins is central to the cell death arm of the UPR pathway. This chapter discusses the recent findings on the involvement of BCL-2 family members in the apoptotic process initiated by ER stress and a related process called autophagy. Understanding the molecular mechanisms involved in ER stress and autophagy could have a profound implications developing new therapies for many ER stress associated diseases and cancer.