The refractoriness of advanced lung cancer to current treatment modalities requires new approaches to reduce the public health burden associated with this disease. One strategy that is currently being tested is chemoprevention, which aims to prevent the development of cancer in populations that are at high risk for cancer due to a variety of genetic or environmental factors. The key to the success of this approach, however, requires the identification of appropriately targeted efficacious, non-toxic agents as well as the methodologies to efficiently test them. Given the lack of success of previous phase III definitive lung cancer chemoprevention trials, there is a need for smaller scale phase II trials with molecular, imaging, or histologic endpoints to demonstrate preliminary safety and efficacy. The identification of molecular pathways critical to lung carcinogenesis offers the opportunity to develop targeted therapies for prevention. Means of optimizing the risk/benefit ratio associated with treatment include regional drug delivery that minimizes systemic toxicities and combination therapies. Identification of the most appropriate cohorts, such as former smokers without ongoing DNA damage due to carcinogen exposure, may uncover benefits that are hidden in a mixed population. Equally important is the identification of appropriate study endpoints that are predictive of patient outcomes such as cancer incidence. Further understanding of lung cancer biology will be critical to the success of future clinical trials.