A critical question is, why do the European studies fail to confirm the US study? Clearly, the answers are complex and uncertain. Differences in power, age, risk, compliance, the use of ERT, and follow-up in the European studies may all be relevant. The efficacy of tamoxifen in BRCA 1 or 2 carriers is an important issue; recent data have shown a DNA repair defect in those with BRCA 1 gene alterations. This finding, coupled with the potential genotoxicity of tamoxifen, is of concern, but the NSABP study did show a significant reduction in breast cancer risk in those with first-degree relatives with breast cancer, including those likely to have a hereditary-predisposition gene. The issue will be clarified when the BRCA 1 or 2 status of these individuals is determined from the stored DNA samples of all participants in the NSABP study. The duration of use of an antiestrogen for prevention is uncertain; the adjuvant trial data for up to 5 years of tamoxifen use showed an effect on contralateral breast cancer prevention extending beyond 5 years, but experimental data show that stopping tamoxifen therapy results in the appearance of new tumors. The long-term use of tamoxifen for prevention carries significant risks. If raloxifene can be given long term, then continuing the prevention of tumors may be possible if raloxifene is proven safe. Should tamoxifen be used outside of a clinical trial? The FDA has approved its use to "delay" breast cancer so it can be prescribed for any patient at increased risk for breast cancer. The word prevention has been the subject of polemics. Every day that breast cancer is delayed is a day that it is prevented. Risk reduction is technically a more accurate phrase but lacks meaning to many women. Novel approaches to chemoprevention are being explored. Naturally occurring compounds or their analogues are being assessed. Based on experimental studies, the vitamin A analogue 4-hydroxyphenyl retinamide (4-HPR) was shown to delay and reduce carcinogen-induced breast cancer. A randomized clinical trial of 4-HPR is being tested in women in Italy to reduce contralateral breast cancer, but no results are available. New approaches using substances derived from plants, such as vegetables, are being pursued. Based on epidemiologic studies, investigators have proposed that an estrogen metabolite, C16 alpha-hydroxyesterone (16 alpha-OHE1), may have estrogen-stimulating and DNA-damaging properties of mammary epithelial cells. Strategies to reduce 16 alpha-OHE1 have been explored. Indole-3-carbinol, found in high concentration in cruciferous vegetables (i.e., cabbage, cauliflower, broccoli, rabe, brussels sprouts, kale, and bok choi), has been shown to reduce mammary cancer in rodent models and induces a metabolic pathway competing with 16 alpha-OHE1, which increases C-2 hydroxyesterone and thereby reduces substrate available for the 16 alpha-OHE1 pathway. Indole-3-carbinol has a good short-term safety profile. The minimum effective dose that favorably perturbs the ratio between 16 alpha-OHE1 and 2-OHE1 has been determined, and a pilot feasibility trial is in progress in women at risk for breast cancer at Strang Cancer Prevention Center. Future research will identify single or a combination of agents that may significantly reduce the risk for breast cancer without toxicity. A better understanding of the steps involved in the progression of normal breast cells toward cancer will permit the development of strategies to reduce the incidence of and mortality from breast cancer, with the ultimate goal of prevention.