Cancer cells are exposed to 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 in the acquisition of malignant characteristics that ultimately lead to cancer progression. Although, several reports describe the relevance of the UPR in tumor growth, the possible crosstalk with other cancer-related pathways is starting to be elucidated. The Forkhead Box O (FoxO) subfamily of proteins has a major role in cancer progression, where chromosomal translocations and deregulated signaling lead to loss-of-function of FoxO proteins, contributing to tumor progression. 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, studies linking a crosstalk between the UPR and FoxO proteins in other diseases, including neurodegeneration and metabolic disorders is provided.