Respiratory epithelium carcinogenesis is currently considered as the phenotypic aspect of serial genetic and epigenetic aberrations resulting in deregulation of cellular homeostasis. Recent data indicate that DNA demethylating agents and histone deacetylase inhibitors might act synergistically for the prevention of cancer development throughout the carcinogen-exposed epithelium. Preliminary clinical trials have shown encouraging results using these new molecules in lung carcinomas therapeutics. However, the caveats that should be overtaken for efficacious antitumour activity have also emerged. Setting the context in which epigenetic modifications contribute to carcinogenesis evolution is of paramount importance in order to optimize the potency of the current and future epigenome targeting agents.