Tumors expressing either estrogen receptor-alpha (ER; ESR1) and/or the progesterone receptor (PR) represent the most prevalent breast cancer molecular subtype. Patients diagnosed with this form of breast cancer are generally treated with a drug that targets estrogen receptor action. While these drugs are highly effective in improving overall survival for many of these patients, a significant proportion will eventually experience a recurrence of their breast cancer. For most of these women, recurrence will arise after their first 5 years of endocrine therapy. Since there would be no tumor to recur if the treatment had successfully eradicated all diseases, a significant component of the biology of recurrent ER+ breast cancer is related to drug resistance, whether present initially within the cells (de novo resistance) or acquired by the cells in response to treatment (acquired resistance). The acquisition of endocrine resistance is explored here from the perspective of the unfolded protein response (UPR), which plays a central role as a key integrator of response to these treatments. Evidence for upregulation of prosurvival UPR signaling in acquired resistance is presented, as are some of the cellular effects of blocking ER action that lead to UPR induction. From a systems biology perspective, integrative UPR signaling can coordinate several modular functions within breast cancer cells, including apoptosis, autophagy, and proliferation, which contribute directly to the determination of cell fate outcomes in response to treatment.