Histone deacetylases (HDACs) play a central role in the epigenetic regulation of gene expression. Aberrant activity of HDACs has been found in several human cancers leading to the development of HDAC inhibitors (HDACi) as anti-tumors drugs. In fact, over the last years, a number of HDACi have been evaluated in clinical trials; these drugs have the common ability to hyperacetylate both histone and non-histone targets, resulting in a variety of effects on both cancer cells and immune responses. Clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a better clinical efficacy of these drugs in hematological malignancies. In this review, will be highlighted the mechanisms of action underlying the clinical responses obtained with these drugs and the doubts regarding the use of HDACi in cancer therapy.