Tamoxifen has proven to be beneficial in the chemoprevention of breast cancer in women at increased risk for the disease. Other compounds that mediate the estrogen pathway remain to be tested for clinical efficacy. The mechanism of action, efficacy, and dose response of the estrogen modulators is determined by the hormonal milieu of the host which should be considered in the early clinical trials for dose range finding studies and surrogate endpoint biomarker (SEB) evaluation. This review presents the hormonal effects to consider in the clinical testing of an agent in premenopausal vs. postmenopausal cohorts. Recommended SEBs that may be evaluated in Phase I/II clinical trials of estrogen modulators for breast cancer chemoprevention are presented.