Endoplasmic reticulum stress (ER stress) is characterized by the accumulation of misfolded and unfolded proteins in the ER lumen. To mitigate the imbalanced ER protein-folding capacity, cells activate the unfolded protein response (UPR) pathway to re-establish ER homeostasis. Mild or early ER stress is cytoprotective and activation of the UPR pathway and autophagy may be beneficial for the survival of tumor cells. However, persistent and severe ER stress may be detrimental to the tumor cells, as excessive ER stress responses trigger cell death processes such as apoptosis. It is now commonly acknowledged and established that various ER stress-related proteins and pathways are dysregulated during the initiation and development of cancer. Hence, based on this rationale, various classes of anticancer therapeutic agents have been developed targeting the ER stress pathways. This chapter highlights the current understanding of the signaling pathways of ER stress, the role of the UPR pathway in cancer development, and the relevant therapeutic targets and experimental compounds in cancer. Some of the challenges of targeting this pathway in cancer are deliberated.