Several novel targets are currently being evaluated both preclinically and clinically for the prevention of prostate cancer. Four divergent and novel approaches were discussed at the National Cancer Institute–sponsored workshop entitled, “New Clinical Strategies in Prostate Cancer Prevention.” These interventions are further categorized into soy protein–based serine-protease inhibitors that reduce superoxide-induced DNA damage, and molecularly targeted approaches that are directed toward endothelin-1 expression/overexpression, peroxisome proliferator–activated receptor ligands, and insulinlike growth factors. Understanding each of these approaches has offered insights into the process of malignant transformation of prostatic epithelium, and further illustrates the difficulties of developing new agents in the treatment and prevention of prostate cancer. Close scrutiny of the clinical data emerging with these approaches, including validation of biologic endpoints, is required before large-scale prevention studies with these novel agents and targets can be considered.