The indolent nature of estrogen-dependent breast cancer is the most important obstacle for development of new adjuvant endocrine treatments. Clinical trials require thousands of study participants and at least a decade of clinical investigation. How can we be sure that a new endocrine agent warrants this extraordinary level of investment? Traditionally, we have relied on advanced breast cancer trials to determine which drugs are suitable for adjuvant studies. However, with endocrine agents the high incidence of resistance in metastatic breast cancer may mask important advances in efficacy. Recent clinical results with the aromatase inhibitor letrozole suggest that neoadjuvant endocrine therapy is a highly informative additional approach to consider when planning adjuvant studies. In this report, new neoadjuvant endocrine therapy study designs are discussed that address the following issues: (a) the scientific opportunities afforded by gene microarray studies and other genetic technologies to investigate the molecular basis of estrogen-dependent breast cancer; (b) studies that address critical drug development questions as a prelude to adjuvant studies; and (c) the conduct of randomized trials that compare neoadjuvant chemotherapy with neoadjuvant aromatase inhibitor therapy to establish a place for neoadjuvant endocrine therapy in routine clinical practice.