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The endoplasmic reticulum (ER) stress response constitutes a cellular process that can be triggered by a great variety of conditions that cause imbalances in intracellular homeostasis and threaten proper cell functioning. In response, the ER stress response activates an adaptive effort aimed at neutralizing these threats and reestablishing homeostasis. However, if these countermeasures are unsuccessful and severe imbalances persist, the ER stress response may abandon its pro-survival efforts and instead may initiate a pro-apoptotic program to eliminate the faulty cell for the benefit of the organism as a whole. Because vigorous growth of malignant tumors may create stressful conditions, such as hypoglycemia, hypoxia, or accumulation of misfolded proteins during revved up protein synthesis, the adaptive, pro-survival components of the ER stress response system (e.g., GRP78/BiP) are frequently found chronically activated in tumor cells. This differential to non-stressed normal cells has been proposed to represent an Achilles’ heel of tumor cells that may be exploitable by therapeutic intervention. In this model, the goal would be to further aggravate the pre-existing stress conditions in tumor cells with appropriate pharmacological agents, so that the already engaged pro-survival mechanism would be overwhelmed and the ER stress response forced to switch to its pro-apoptotic mode (e.g., CHOP/GADD153). This review will discuss the principle of pharmacological ER stress aggravation, and will present preclinical models with promise for cancer therapeutic applications.