Advances in cell and molecular biology have increased our understanding of the multiple events that lead to the development of lung cancer. The field cancerization theory suggests that multiple genetic abnormalities occur throughout the respiratory epithelium as a result of long-term carcinogen exposure. Because of this diffuse injury throughout the lung, systemic therapy that could halt or reverse the development of cancerous changes may be effective in preventing lung cancer. This article summarizes the chemoprevention agents that have been used in clinical trials to prevent lung cancer of the head and neck. Biomarkers that have been suggested as intermediate end points in evaluating the effectiveness of chemoprevention agents are also discussed.