An aggressive approach to breast cancer control based on preventing the disease must complement efforts at effective treatment. To date clinical trials testing new chemopreventative agents have not generally met with the kind of success expected. A wide range of new breast cancer chemopreventative agents are poised to be tested in clinical trials. We review these novel agents and approaches, including those for which clinical trials have been initiated and those that are promising in the preclinical arena. Further progress in this area requires not only new agents, but novel methods for screening for risk assessment, sampling and development of intermediate biomarkers. We review these novel potential surrogate endpoints, including new imaging-techniques, breast sampling approaches, and methods to assess biomarkers in breast epithelium. Factors that could contribute to a meaningful choice of the chemopreventive agents and the design of clinical trials are discussed.