The endoplasmic reticulum (ER) produces, folds, and modifies proteins before they reach their final destinations. The unfolded protein response (UPR) is initiated when there is, in the ER, an increase of misfolded or unfolded proteins. Cancer cells are subjected to oxidative stress, glucose deprivation, hypoxia, insufficient amino acid supply, and a lack of growth signals, all of which impair protein processing in the ER. These circumstances can lead to the accumulation of altered proteins, causing ER stress and activating UPR. The homeostatic UPR induces at gene protein level modifications that help cellular adaptability and growth. If these activities are unsuccessful to solve ER stress, a fatal UPR program starts, leading to cellular death. This chapter condenses the emerging data that tumor cells are susceptible to ER stress and responsive to therapies that target UPR pathways.