Stress in the tumor microenvironment in the form of hypoxia and low glucose/amino acid levels activates the evolutionarily conserved cellular adaptation program called the unfolded protein response (UPR) promoting cell survival in such conditions. Our recent studies showed that cell autonomous stress such as activation of the proto-oncogene MYC/c-Myc, can also trigger the UPR and induce endoplasmic reticulum (ER) stress-mediated autophagy. Amelioration of ER stress or autophagy enhances cancer cell death in vitro and attenuates tumor growth in vivo. Here we will discuss the role of the UPR and autophagy in MYC-induced transformation. Our findings demonstrate that the EIF2AK3/PERK-EIF2S1/eIF2α-ATF4 arm of the UPR promotes tumorigenesis by activating autophagy and enhancing tumor formation. Therefore, the UPR is an attractive target in MYC-driven cancers.