INTRODUCTION: Epigenetic aberrations play an important role in lung carcinogenesis. Chromatin deacetylation is a fundamental mechanism of gene silencing. Histone deacetylase (HDAC) inhibitors are an emerging class of antineoplastic agents that enable the accessibility of DNA to transcription factors, therefore promoting gene expression. Entinostat is a selective HDAC inhibitor that has shown anti-neoplastic activity and tolerability in hematologic and solid tumors, including lung cancer. AREAS COVERED: This article summarizes the pharmacokinetics, pharmacodynamics, mechanisms of action, safety, tolerability, pre-clinical studies and clinical trials of the HDAC inhibitor entinostat, as a novel promissory agent for the treatment of NSCLC. EXPERT OPINION: The field of targeted therapy has increased in lung cancer. However, even now with the current FDA-approved agents, < 15% of patients benefit from these interventions and we are still far from curing lung cancer. New targets are needed. Either in combination with cytotoxic drugs, epigenetic therapy or other molecular targeted drugs, entinostat represents a new potential agent for the treatment of non-small cell carcinomas. However, the preliminary safety and efficacy results from several clinical trials still need to be validated in large Phase III trials.