Chemoprevention of breast cancer has long been an attractive goal. However, the women most likely to benefit from chemoprevention, women at high risk for breast cancer, have traditionally been difficult to identify. The increased incidence of proliferative breast disease (PBD), associated with an increased risk of developing breast cancer and the identification of the BRCA1 and BRCA2 breast cancer susceptibility genes have provided the opportunity for identification of high risk women. Recent chemopreventive randomized clinical trials have demonstrated that antiestrogens, in particular tamoxifen, and retinoids are among the most effective chemopreventive agents. Adjuvant dietary modifications have also been considered for investigation based on epidemiological and preclinical observations that links high-fat diet to mammary tumorigenesis. In future clinical trials, monitoring of molecular markers of genetic instability through novel laboratory techniques will provide sensitive surrogate endpoint biomarkers (SBEs) to evaluate efficacy of chemopreventive interventions.