In cells, incorrectly folded proteins or compromised protein turnover induce cellular stress known as endoplasmic reticulum (ER) stress. Significantly, ER stress plays an important role in numerous physiological and pathological conditions, including degenerative diseases and cancer. In an attempt to resolve ER stress cells activate a response known as the unfolded protein response (UPR). While, initially a protective response, the UPR can induce cell death if ER stress is not overcome. As the precise molecular mechanisms that regulate ER homeostasis and UPR-related cell death remain elusive, I focused my initial studies on understanding these processes. In the course of this study it was discovered that autophagy, a process utilized by cells to degrade misfolded and/or damaged proteins, is important for restoring proper ER function. However, unabated autophagy can promote cell death. As autophagic protein degradation is ultimately carried out by lysosomal hydrolases, I also studied how perturbations within lysosomes affect ER function and cellular homeostasis. An endogenous inhibitor of lysosomal cathepsins known as squamous cell carcinoma antigen 1 (SCCA1), a member of the serine protease inhibitor (Serpin) family of proteins, was expressed in cells to modulate lysosomal function. Significantly these studies revealed that SCCA1 is able to protect cells against lysosomal injury resulting from DNA alkylating agents and hypoosmotic stress. This protection is due to SCCA1’s ability to inhibit lysosomal rupture, thus preventing cytotoxic release of lysosomal hydrolases into the cytosol. Conversely, due to the inhibition of lysosomal protein degradation, SCCA1 promotes cell death in response to ER stress. This SCCA1-mediated cell death in response to ER stress is carried out by intracellular aggregation and subsequent activation of caspase-8. Hence, on one hand SCCA1 inhibits cell death induced by lysosomal damage, while on the other hand it sensitizes cells to ER stress by activating caspase-8. Our studies have thus uncovered a novel mechanism of cell death in response to ER stress. Given that SCCA1 expression is elevated in numerous cancers, these findings may offer insight into selective treatment strategies for SCCA1 expressing cancers.