The drug-dependent induction of premature senescence in neoplastic cells is considered per se an important tumor suppressive mechanism. DNA demethylating agents recently introduced in clinical trials, such as 5-aza-cytidine (Decitabine) and its derivatives, have been extensively characterized in recent years as antiproliferative compounds that act through multiple mechanisms, which have not yet been fully clarified. We recently analyzed the introduction of Decitabine in therapy for malignant pleural mesothelioma (MPM) observing that, despite the ability to induce profound biological effects in MPM cells, the drug failed to generate a massive apoptotic response. Since one of the most intriguing aspects of DNA demethylating agents is the possibility to accelerate the senescent response of tumor cells, we investigated the hypothesis of Decitabine inducing, in vitro, the premature aging of MPM cells.