Epigenetic mechanisms, including histone deacetylation, are commonly deregulated in cancer. Histone deacetylases (HDACs) play an important role in tumorigenesis and their value as therapeutic targets has been under intense investigation in recent years. In addition to classical HDACs (HDAC classes I, II, and IV), sirtuins (class III HDACs) are currently in the spotlight of cancer research showing promise as cancer biomarkers and therapeutic targets. Translating research knowledge into the clinical setting is, however, a challenging and demanding task. This review describes the association between HDAC deregulation and cancer promotion and highlights recent advances in the use of HDAC inhibitors in the management of neoplastic diseases, with emphasis on urological tumors. Sirtuins' bivalent role in tumor development and therapeutic agents targeting these molecules will be also addressed.