Chemoprevention is an innovative area of cancer research that focuses on the development of pharmacological, biological, and nutritional interventions to prevent, reverse, or delay carcinogenesis. Over the past two decades the Division of Cancer Prevention of the US National Cancer Institute has organized a research and development program to provide resources and infrastructure to the research community for the clinical evaluation of potential cancer preventive agents. This program now encompasses preclinical agent and molecular target identification, in vitro and in vivo screening, efficacy and intermediate endpoint testing, pharmacology and toxicology assessments, and finally chemical synthesis and manufacturing leading to Investigational New Drug applications and clinical studies. In this review, examples of agents currently in development, preclinical testing models, and phase 1 and 2 clinical studies are described. Continued commitment to cancer prevention will significantly reduce the economic and medical burden of cancer.