Vast numbers of individuals who have stopped smoking have already been exposed to critical amounts of tobacco combustion products and are at significant risk of developing lung cancer. If these individuals are diagnosed with regional or distant metastatic disease this condition is not typically curable with existing systemic therapy. The need for more effective tools to detect and intervene with early lung cancer detection is a pressing public health priority. A major challenge in this regard is the development of safe and effective lung cancer chemoprevention. The factors influencing the development of this new clinical tool are reviewed in the context of existing trends for lung cancer care. Existing pharmaceutical efforts have involved evaluation of existing treatments for advanced cancer or other disorders in early lung cancer. The paper describes approaches to tailor chemoprevention development specifically to the biological, pharmacological and anatomical realities of this most lethal cancer.