Valproic acid (VPA) is frequently featured in the treatment of bipolar disorder and epilepsy and has entered the clinical field for decades with established pharmacokinetics and a safe side effects profile. It has now been viewed as a new epigenetic therapeutic agent in cancer therapy. VPA is a class I and IIa selective histone deacetylase inhibitor, which involves cellular and biological pathways that influence carcinogenesis and prognosis, including cell cycle progression, apoptosis induction and differentiation. As a potent HDACs inhibitor, a subclinical dosage of VPA can reversibly cause antiproliferation effects in vitro without causing much harm to healthy tissues. In clinical trials, VPA shows positive results when combined with chemotherapy and radiotherapy by enhancing responsiveness and cytotoxicity, reducing therapy resistance. The use of VPA as adjuvant therapy in cancer treatment could bring new developments to classical anti-cancer therapy.