There is clearly a need for novel breast cancer chemopreventive agents with enhanced potency and specificity with little or no side effects. To this end, several new chemical moieties have been synthesized or isolated from natural sources. In this review, we have described some agents currently in use or under development for treatment or prevention of breast cancer, as well as our own strategies for the discovery of natural product modulators of estrogen biosynthesis and function. In particular, bioassay-guided fractionation of active plant extracts is a unique method for identifying agents with novel mechanisms of action, some of which should be useful for prevention of human cancer. Further, with the advent of combinatorial chemistry and high throughput screening, even greater progress may now be expected with natural product leads.