Physiological stresses, such as hypoxia and oxidative stress, induce protein misfolding in the endoplasmic reticulum (ER). If proteasome degradation fails to remove the misfolded proteins, these proteins accumulate in the ER, triggering the unfolded protein response (UPR). UPR involves a series of responses, such as the suppression of global protein synthesis and the select expression of a set of proteins to reduce ER stress and restore the homeostasis of ER. In different stages of tumor development, hypoxia occurs and UPR is initiated. The roles of UPR in cancer development are complex, involving angiogenesis, cell survival and proliferation. The current knowledge of the molecular mechanisms involved in UPR, particularly its role in the development of cancer, is discussed.