Lung cancer is both the most frequent and the most lethal form of cancers worldwide. The vast majority of lung cancers are directly imputable to one risk factor, tobacco smoke, highlighting the preventability of this disease. While tobacco control is the most efficient lung cancer prevention strategy, it seems unrealistic to expect every smoker to quit, owing to the addictiveness of this product and the low success rate of tobacco cessation procedures. Therefore, the development of lung cancer chemoprevention strategies is essential. Among the numerous pathways that can be targeted, NF-κB, a transcription factor that controls inflammation, is particularly interesting. The present work covers various aspects of the preclinical drug discovery process aiming at developing a safe and efficient lung cancer chemopreventive drug from natural sources. It includes the discovery of potent NF-κB inhibitors, the elucidation of their mechanism of action, and the evaluation of their in vivo efficacy.