Cancer cells are exposed to several adverse conditions within the tumor microenvironment that challenge cells to adapt and survive. Several of these homeostatic perturbations insults alter the normal function of the endoplasmic reticulum (ER), resulting in the accumulation of misfolded proteins. ER stress triggers a conserved signaling pathway known as the unfolded protein response (UPR) to cope with the stress or trigger apoptosis of damaged cells. The UPR has been described as a major driver of the acquisition of malignant characteristics that ultimately lead to tumor progression. Although, several reports describe the relevance of the UPR in tumor progression, the possible crosstalk with other cancer related pathway is starting to be elucidated. The Forkhead Box O (FoxO) subfamily of proteins has a major role in cancer progression. Chromosomal translocations and deregulated signaling lead to loss-of-function of FoxO proteins, contributing to tumor progression through several mechanisms. Here we discuss the homeostatic connection between the UPR and FoxO proteins and its possible implications to tumor progression and the acquisition of several hallmarks of cancer. In addition, a parallel with other diseases related to chronic ER stress, including neurodegeneration and metabolic disorders, is provided.