The endoplasmic reticulum (ER) stress response, in combination with autophagy, represents an adaptive mechanism to support cellular survival in response to a great variety of detrimental conditions, such as low nutrient levels, hypoxia, calcium imbalance, or accumulation of misfolded proteins. However, when stress conditions become too severe and excessive, this cellular stress response system turns on its pro-apoptotic module, which then gains dominance and triggers cell death. In tumor cells, the cell-protective features of the ER stress response appear to be chronically activated and thus provide support for continuous proliferation and survival even under adverse microenvironmental conditions, which may include chemotherapy. However, persistent activity of these pro-survival pathways primarily in tumor cells may provide a window of opportunity for therapeutic intervention that is principally aimed at these tumor-specific conditions. Appropriate therapeutic regimens would seek to further aggravate this already engaged system in tumor cells in order to exhaust its protective features and instead trigger its pro-apoptotic module. There is accumulating evidence that this can indeed be accomplished, and that tumor-specific ER stress can be exploited by treatment with select pharmacological agents. The principles of this promising new approach to cancer therapy, as well as representative ER stress-aggravating compounds, will be presented in this review.