Oxygen deprivation (hypoxia) is a common feature of tumors that is associated with treatment resistance and poor patient survival. Hypoxia perturbs the oxidative environment within the endoplasmic reticulum (EnR), limiting protein folding capacity. This restriction causes an accumulation of unfolded proteins in the EnR and activation of a stress response pathway, termed the unfolded protein response (UPR). Signals from the UPR culminate in repression of general protein translation. Paradoxically, a small number of transcripts are selectively translated under these conditions. One of these transcripts encodes Activating Transcription Factor 4 (ATF4). In tumors, ATF4 expression is detected in hypoxic and nutrient-deprived regions. ATF4 promotes metabolic homeostasis and cancer cell survival by transcriptionally regulating numerous processes including amino acid uptake, antioxidant biosynthesis, and autophagy. These changes confer ATF4-expressing cells with a multidrug resistance phenotype and the ability to tolerate adverse stresses of the tumor microenvironment. However, under conditions of persistent and unresolved stress, ATF4 transcriptional reprogramming becomes pro-apoptotic. Therapeutic modulators of ATF4 signaling have the potential to modify these properties by diminishing adaptive phenotypes in cancer cells. Reprogramming cancer cells in this way can improve tumor sensitivity to anticancer treatments including chemotherapy, immunotherapy, and radiotherapy.