Despite the established role of insulin-like growth factor binding protein-3 (IGFBP-3) as a growth inhibitor in vitro, a high level of IGFBP-3 in breast tumor tissue is associated with the stimulation of xenograft growth in mice and poor prognosis in patients. To understand the contribution of IGFBP-3 to breast cancer progression, tandem affinity purification was used to identify novel interacting proteins. The endoplasmic reticulum protein, glucose-regulated protein 78 (GRP78), was shown to bind to IGFBP-3, confirmed by colocalization, coimmunoprecipitations, glutathione S-transferase (GST) pulldowns and a nanomolar binding affinity. GST pulldowns also indicated that the GRP78 ATPase domain mediated the interaction with IGFBP-3. The critical roles of GRP78 in the unfolded protein response and macroautophagy led to an investigation of possible links between IGFBP-3, GRP78 and cellular stress responses. IGFBP-3 was found to stimulate the survival of breast cancer cells subjected to glucose starvation and hypoxia. Pharmacological inhibitors and small interfering RNA knockdown established that the increased survival of IGFBP-3-expressing cells was dependent on an intact autophagy response, as well as GRP78. The contribution of autophagy was confirmed by the demonstration that IGFBP-3 expression increases both the formation of autophagic puncta and flux through the system. In conclusion, we have shown that IGFBP-3 stimulates autophagy and thereby promotes the survival of breast cancer cells exposed to conditions that represent the adverse microenvironments encountered by solid tumor cells in vivo.