The development of chronic and fluctuating hypoxic regions in tumors has profound consequences for malignant progression, response to therapy and overall patient survival. Understanding the events involved in hypoxia tolerance will offer new opportunities for antitumor modalities. A universal response of tumor cells to hypoxia is a rapid and substantial decrease in the rates of macromolecular synthesis. Hypoxia induces phosphorylation of the translation initiation factor eIF2alpha on Ser51 via activation of the endoplasmic reticulum (ER) resident kinase PERK and that this modification is required for the rapid downregulation of global protein synthesis by this hypoxic stress. PERK-dependent phosphorylation of eIF2alpha is one component of the Unfolded Protein Response (UPR), a coordinated program that promotes cell survival under conditions of ER stress. Inactivation of PERK or eIF2alpha phosphorylation impairs cell survival under hypoxia, and transformed cells with inactivating PERK or eIF2alpha mutations form tumors in nude mice that are slower growing, and have higher levels of apoptosis in hypoxic areas compared to tumors with an intact UPR. Expression of the transcription factor ATF4, a downstream effector of eIF2alpha phosphorylation, is also upregulated by hypoxia in vitro and in human tumors and increases hypoxia tolerance. A second UPR pathway mediated by activation of IRE1 and its downstream target XBP1 is also required for hypoxia tolerance in vitro and for tumor growth. These results reveal a critical role for UPR activation for tumor cell resistance to hypoxia and tumor growth promotion and suggest that the UPR may be an attractive target for anti-tumor modalities.