Improvement in endocrine therapy for estrogen receptor (ER)-positive breast cancer will require prevention or modulation of resistance, based on identification and targeting of the responsible molecular mechanisms. Our approach to this problem has been to focus on neoadjuvant endocrine treatment because that permits comparative evaluation of pretreatment tumor biopsies and surgical tumor specimens. We have begun utilizing this clinical paradigm by exploring semiquantitative changes in the expression of molecular markers within tumors treated with either tamoxifen or the aromatase inhibitor letrozole in a randomized trial. This investigation is beginning to elucidate the influence of growth factor pathways that interact with the ER, especially HER1 (epidermal growth factor receptor [EGFR]) and HER2. The results indicate that the distinct mechanisms by which tamoxifen and letrozole inhibit ER signaling may produce quite marked differences in clinical and biomarker outcomes in the subset of tumors that coexpress HER1 and/or HER2 with ER, favoring estrogen-deprivation therapy. Ongoing investigations are examining gene expression profile changes associated with neoadjuvant endocrine therapy, as well as inhibitors of growth factor signaling that may modulate tamoxifen resistance.