Tumor hypoxia confers resistance to many modalities of anticancer therapy. The endoplasmic reticulum (ER) is highly sensitive to severe hypoxic stress and results in the activation of the unfolded protein response. ATF4 is the main transcriptional regulator of the cellular hypoxic response to the Unfolded Protein Response (UPR) and activates genes that promote restoration of normal ER function and survival under hypoxia. Elevated expression of ATF4 is associated with resistance to current chemotherapeutic drugs including DNA-interactive and damaging agents, nonsteroidal anti-inflammatory drugs and proteasome inhibitors. ATF4 decreases the antitumor activity of chemotherapy by mechanisms involving expression of genes involved in oxidative stress resistance, redox homeostasis and inhibitors of apoptosis. ATF4 plays also a crucial role in resistance to proteasomal inhibitor bortezomib (PS-341) by the induction of prosurvival pathways, such as autophagy, that can relieve the protein overload in bortezomib treated cells. Inhibition of ATF4 represents an attractive stand-alone therapy as well as an opportunity to enhance the efficacy of current chemotherapeutic agents without causing high tissue toxicity to normal tissues.