Histones are highly alkaline proteins of cell nuclei that package and order DNA into structural units called nucleosomes. The balance between the acetylation and deacetylation of hystones is mediated by two different sets of enzymes: histone acetyltransferases and histone deacetylases (HDACs). HDAC inhibitors, a novel class of anticancer agents, acting by regulating chromatin structure and function, induce acetylation of histones, which ultimately results in apoptosis and cell cycle arrest, modulate anticancer immunity and inhibition of angiogenesis. HDAC inhibitors are being clinically investigated for the treatment of several hematological and solid tumors. The potential role of HDAC inhibitors in the treatment of advanced non-small-cell lung cancer patients, including their clinical effectiveness and future developments, is discussed here.