Over the last 20 years tamoxifen, a selective estrogen receptor modulator, has been shown to be of clinical benefit to patients with advanced and resected hormone receptor-positive breast cancer. Tamoxifen has also been evaluated as a risk-reducing agent among patients at a high risk for the development of breast cancer and found to be effective, although it is associated with untoward adverse events (ie, stroke, venous thrombosis, and endometrial cancer). Recent analysis of National Surgical Adjuvant Breast and Bowel Project tamoxifen trials confirms that an increased risk for developing various endometrial malignancies exists across these protocols. Raloxifene, a selective estrogen receptor modulator available to treat osteoporosis, may also reduce the risk for developing breast cancer. The National Surgical Adjuvant Breast and Bowel Project is now comparing the risk-reducing activities of tamoxifen and raloxifene in women considered to be at a high risk for developing breast cancer. As newer potential risk-reducing agents are identified and placed into clinical prevention trials, patient selection, trial implementation methods, and accrual strategies must be developed to insure both that appropriate accrual targets are achieved and that women at clinically significant risk levels are accrued.