Non-small-cell lung cancer (NSCLC) arises from a complex series of genetic and epigenetic changes leading to uncontrolled cell growth and metastases. The exponential growth in the level of research about the histone deacetylase (HDAC) enzymes, responsible for deacetylating core nucleosomal histones and other proteins, has been driven by the ability of HDAC inhibitors to modulate transcriptional activity. As a result, this therapeutic class is able to block angiogenesis and cell cycling, and promote apoptosis and differentiation. The mechanisms resulting in the antiproliferative biologic effects of these agents are not yet known. Clinical experience indicates these agents generally well tolerated, and active in several haematological and solid tumours. HDAC inhibitors, under clinical evaluation in the treatment of NSCLC patients, are pivanex, CI-994, vorinostat, and LBH589. Here, we discuss about the potential role of HDAC inhibitors focusing on their activity, tolerability, efficacy and future development, in the treatment of NSCLC.