Mammalian cells have evolved multiple adaptive pathways, referred to as the unfolded protein response (UPR), that allow them to respond to perturbations in endoplasmic reticulum (ER) homeostasis. One major pro-survival factor is the ER chaperone GRP78, also referred to as HSPA5 or BiP. In addition to assisting in the assembly and quality control of ER proteins, GRP78 regulates UPR signaling in response to ER stress. Mechanisms for the cytoprotective effects of GRP78 include suppression of pro-apoptotic pathways, maintenance of ER structural integrity and stress-induced autophagy. GRP78 is overexpressed in a wide variety of human cancers and is associated with poor prognosis, metastasis and resistance to therapy. Mouse models with genetically altered GRP78 provide valuable systems to interrogate the role of GRP78 in tumorigenesis and metastasis. Targeted knockout of the GRP78 allele in mouse models of cancer revealed that GRP78 is critical for tumor proliferation, survival and tumor angiogenesis. Conditional knockout of GRP78 in endothelial cells further establishes that GRP78 haploinsufficiency impedes neovascularization during tumor growth and metastasis, with minimal effect on normal tissue microvessel density. Knockdown of GRP78 in human endothelial cells suppresses proliferation, survival and migration. These studies underscore the potential value of GRP78 as a novel therapeutic target for dual anti-tumor and anti-angiogenesis activity. Stress induction of GRP78 in tumors leads to resistance to a wide variety of therapeutic agents, whereas suppression of GRP78 sensitizes them to the treatment. Furthermore, evidence is emerging that GRP78, traditionally regarded as an ER resident protein, is preferentially expressed on the surface of tumor cells but not in normal organs. Cell surface GRP78 serves as an upstream regulator of the PI3K/AKT oncogenic pathway which is widely implicated in cancer proliferation, survival, migration and resistance. Thus, GRP78 as cell signaling regulator and protector of ER homeostasis, is a prime candidate for therapeutic targeting.