Tamoxifen has been shown to reduce the incidence of estrogen receptor-positive breast cancer by approximately 50% in high-risk women. Similar results are seen for raloxifene, but it has a more favorable side-effect profile. Data on contralateral tumors from women in adjuvant trials treated with aromatase inhibitors suggest that new tumors can be reduced by another 50% with these drugs, suggesting a potential 75% reduction of estrogen receptor-positive tumors when used in a prophylactic manner. Side effects appear to be fewer with the aromatase inhibitors, with no excess of gynecologic (including endometrial cancer) or thromboembolic events, but an increase in fracture risk and joint symptoms does occur. IBIS II is a placebo-controlled prevention trial evaluating 5 years of the aromatase inhibitor anastrozole in high-risk postmenopausal women. The primary end point is breast cancer incidence, but major efforts are also being directed at minimizing any fracture risk.