1. INTRODUCTION Despite focused efforts over the last two decades to further understand the causes of breast cancer, little new information has been gained regarding breast cancer etiology. Risk factors that are ‘‘known’’ explain approximately 40% of the variability in incidence (1); the remaining risks for breast cancer are yet to be determined. Breast cancer appears to be extremely heterogeneous, with multiple factors contributing to the etiology of the disease. It is plausible that a number of lifetime events and exposures, in combination with variability in key genes that metabolize steroid hormones, dietary factors, and chemical carcinogens, as well as those involved in DNA repair, signal transduction, and cell cycle control, are likely to be responsible for carcinogenesis in the breast. The focus of this chapter will be to review known and suspected risk factors for breast cancer, and the possible modification of risk relationships by genetic variability in mechanistic pathways.