Endocrine-tolerant persistence in ER+ breast cancer cells can lead to the emergence of endocrine-resistant disease. Using CRISPR-Cas9 knockout screening, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. Genetic profiling and barcode lineage tracing showed that persistence occurred stochastically. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters and synergized with fulvestrant to induce regression of patient-derived xenografts (PDX). Endocrine-tolerant persisters also showed increased oxidative stress that restrained growth. Endocrine therapy sensitized cells and tumors to the induction of ferroptosis, which was exacerbated by exogenous polyunsaturated fatty acids in vitro. In the endocrine-resistant setting, ER hyperactivation can elicit toxicity. Estrogen-independent growth is enhanced by ER overexpression, which sensitizes cells to estrogen toxicity. ER activation with 17b-estradiol (E2) induced R-loops that drove replication-dependent DNA damage in ER-overexpressing and long-term estrogen-deprived (LTED) cells. DNA fiber analysis suggested that E2 slows replication fork progression in ER-overexpressing cells. PARP proteins have roles in the repair of DNA damage and R-loops. Pharmacological inhibition of PARP with olaparib synergized with E2 against PDX tumors. Olaparib did not affect R-loop abundance in vitro. Although combination treatment with E2/olaparib did not increase DNA damage in PDX tumors, the proportion of replicating cells was decreased, which could reduce the amount of replication-dependent DNA damage. Pre-treatment with olaparib was required to enhance E2-induced DNA damage in vitro, suggesting that PARP inhibition may prime cells for therapeutic response to E2.