Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well-recognized causes. Apart from oxidants (free radicals), cigarette smoke contains such a multitude of (pre)carcinogens that it is astonishing that not every heavy smoker becomes a victim of malignancy. This points to the interindividual variability in susceptibility to carcinogens; several lines of evidence suggest that metabolic factors are involved in such variability. Metabolism of carcinogens as well as the subsequent (multi)steps of carcinogenesis are affected by host factors and governed by the balance between opposing forces, such as metabolic activation and detoxification, formation and scavenging of radicals, and DNA damage and repair, which seem to imply that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione (GSH) plays a crucial role in the detoxification of xenobiotics. N-Acetylcystiene (NAC), an aminothiol and synthetic precursor of intracellular cysteine and GSH, has been used for many years in Europe as a mucolytic drug. Clinically, it is a safe agent without major side effects and has been considered to have a place in cancer prevention, too. The antimutagenic and anticarcinogenic properties of NAC could be ascribed to multiple protective mechanisms, such as NAC nucleophilicity, antioxidant activity, its ability to act as a precursor of intracellular reduced GSH, modulation of detoxification, and DNA repair processes. On these grounds, NAC has emerged as a most promising cancer chemopreventive agent. Since 1988, NAC has been tested in a large European chemoprevention study (EUROSCAN) involving high-risk individuals to prevent the occurrence of a second primary (lung) cancer. Toxicity data of this and other studies confirm that a long-term daily usage of NAC in a 600mg dose is safe and may be recommended for clinical chemopreventive research.