A number of physiologic or pathologic stimuli, such as hypoxia, calcium depletion or oxidative stress, may interrupt the function of endoplasmic reticulum and subsequently cause accumulation of unfolded or misfolded proteins which results in endoplasmic reticulum stress (ERS). ERS maintains cancer cell survival initially, but it may eventually trigger apoptosis etc. if endoplasmic reticulum dysfunction is severe or prolonged. Therefore, the drug research and development based on ERS might be a promising strategy for cancer therapy. Herein, the article introduces the progress of anti-cancer drug discovery based on ERS, summarizes some ERS inducers from natural products and analyzes the problems, as well as the prospect in this area.