Unlike most areas of oncology, prophylactic efforts are unlikely to be subjected to randomized clinical trials. Undergoing prophylactic mastectomy is a personal issue and, even aside from the ethical concerns in randomizing women to such surgery, it is doubtful that any trial randomizing to a surgical prophylaxis arm would be able to accrue effectively. Thus, in the absence of such studies, other approaches are needed to address the challenges of taking care of women who seek prophylactic measures. Such approaches include use of large registries to provide sufficient sample size and thus sufficient statistical power to be able to determine survival benefits of prophylactic intervention. In addition, for women who are not carriers of known breast cancer risk genes, greater research is needed to improve risk stratification beyond the currently available clinical variables of family history and personal history of breast cancer and breast disease. In this regard, research into early molecular changes within the histologically nonneoplastic breast that may be indicative of cellular transformation or identification of single nucleotide polymorphisms in DNA extracted from blood that associate with significant increase in breast cancer risk would be invaluable. Through these multiple avenues, it is hoped that our current broad guidelines for prophylactic mastectomy, which result in substantial overtreatment, can be narrowed to limit such radical therapy only to those women who are highly likely to benefit.