Primary prevention trials have shown that tamoxifen lowers breast cancer incidence by 30-40%. Because of the endometrial risk of tamoxifen and the pro-thrombotic effects of tamoxifen and raloxifene, different strategies are being pursued to improve the risk:benefit ratio of breast cancer chemoprevention. Thus, raloxifene is being compared with tamoxifen in a phase III trial, while the minimal active dose of tamoxifen is being assessed in phase I-II trials. Also, the combination of hormone replacement therapy (HRT) and tamoxifen may reduce the risks while retaining the benefits of either agent. Anastrozole holds promise as a preventive agent based on preliminary results on contralateral breast cancer. The identification of women at increased risk for estrogen receptor (ER)-positive breast cancer due to hormonal and reproductive factors may maximize the therapeutic index of hormonal agents. Finally, new targets that interfere with ER-negative breast carcinogenesis are being sought as one-third of breast cancers will not be preventable by hormonal interventions.