Post-genomic methodologies have provided novel tools for evaluating safety and efficacy of cancer chemopreventive agents. We exposed rats to environmental cigarette smoke (ECS) for 28 days, with or without oral administration of N-acetylcysteine (NAC). As assessed by 32P-postlabelling, ECS caused a 10-fold increase of DNA adduct levels, which were significantly reduced by NAC. Of 518 proteins tested by antibody microarray, ECS stimulated 56 activities involved in stress response, protein removal, cell replication, apoptosis, phagocytosis, and immune response. NAC alone did not change the amounts of any protein, whereas it significantly decreased the amounts of 6 ECS-induced proteins. The intensity of expression of 278 related genes, assessed by cDNA microarray, was significantly correlated with protein amounts. These observed molecular alterations, which can be attenuated by NAC, represent in part adaptive responses and in part reflect mechanisms contributing to the pathogenesis of smoke-related diseases, including lung cancer, asthma, chronic bronchitis, and emphysema.