Histone deacetylase inhibitors (HDACis) have fascinated researchers in almost all fields of oncology for many years owing to their pleiotropic effects on nearly every aspect of cancer biology. Since the approval of the first HDACi vorinostat for the treatment of cutaneous T-cell leukemia in 2006, more than a hundred clinical trials have been initiated with a HDACi as a single agent or in combination therapy. Although a number of epigenetic and nonepigenetic molecular mechanisms of action have been proposed, biomarkers for response prediction and patient selection are still lacking. One of the inherent problems in the field of HDACis is their 'reverse' history of drug development: these compounds reached clinical application at an early stage, before the biology of their targets, HDAC1-11, was sufficiently understood. This review summarizes the current knowledge on the human family of HDACs as drug targets in pediatric and adult brain tumors, the efficacy and molecular action of HDACis in preclinical models, as well as the current status of the clinical development of these compounds in the field of neuro-oncology.