Lung cancer remains a major cause of mortality worldwide, despite advances in surgery, radiotherapy and chemotherapy. Most patients present with advanced disease, and early detection approaches are still experimental. Chemoprevention strategies are therefore essential. Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress or prevent progression to invasive cancer. The present review will provide an update on lung cancer clinical chemoprevention trials as well as the molecular basis of lung carcinogenesis. A better knowledge of lung carcinogenesis is obviously fundamental to improve chemoprevention strategies. Identification of molecular defects involved in premalignant lesions and/or invasive cancer could lead to clinical studies with new molecular-targeted agents (mainly tyrosine kinase inhibitors, farnesyl-transferase inhibitors and/or antiangiogenic molecules) and the development of surrogate biomarkers. Such biomarkers would be essential to detect high-risk patients, select adequate chemoprevention strategies and monitor drug efficacy. New chemoprevention trials are planned with collaborative efforts of researchers involved in fundamental or clinical studies.