Significance Late-stage estrogen receptor α (ERα)-positive breast and ovarian cancers exhibit many regulatory alterations and therefore resist therapy. Our novel ERα inhibitor, BHPI, stops growth and often kills drug-resistant ERα + cancer cells and induces rapid and substantial tumor regression in a mouse model of human breast cancer. BHPI distorts a normally protective estrogen–ERα-mediated activation of the unfolded protein response (UPR) and elicits sustained UPR activation. The UPR cannot be deactivated because BHPI, acting at a second site, inhibits production of proteins that normally help turn it off. This persistent activation converts the UPR from protective to lethal. Targeting therapy-resistant ERα-positive cancer cells by converting the UPR from cytoprotective to cytotoxic may hold significant therapeutic promise.