Patients with locally advanced breast cancer are frequently treated with preoperative (neoadjuvant) systemic therapy to downstage the tumor and improve surgical outcomes. The conventional approach has been to administer chemotherapy but for estrogen receptor-positive (ER+) tumors endocrine therapy is a logical alternative. Neoadjuvant endocrine therapy was initially investigated in older or medically frail individuals who were poor candidates for cytotoxic drugs. However, indirect comparisons suggest that preoperative endocrine therapy with an aromatase inhibitor promotes breast conservation probably as frequently as chemotherapy. As a result, primary systemic therapy with an aromatase inhibitor is now being explored in a younger, healthier population. A key advance would be the development of predictive biomarkers so that this treatment can be more confidently incorporated into routine clinical practice. Interestingly, it seems logical that such a test also would identify patients with highly endocrine therapy-responsive tumors that do not derive much benefit from adjuvant chemotherapy. The American College of Surgeons Oncology Group and the Central Clinical Trials Unit recently activated a neoadjuvant aromatase inhibitor trial with these aims in mind. In this review, we outline the rationale for preoperative endocrine therapy, and consider predictive models for endocrine therapy responsiveness in this setting.