Histone modifications play major regulatory roles in many genetic events such as transcriptional activation and elongation, silencing and epigenetic cellular memory, level of histone acetylation is determined by the combined activities of two enzyme families including the histone acetyltransferases (HATs) and deacetylases (HDACs). Deacetylation of histone contributes to the development of malignancies. A number of HDACs inhibitors have been identified that induce cancer cells in culture to undergo growth inhibition, differentiation, and apoptosis in a wide variety of transformed cells including melanom, leukemia, prostate, lung, ovarian, breast and colon cancers. HDAC inhibitor valproic acid (VPA) is a short chain fatty acid with a long history of clinical use as an anticonvulsant drug which inhibits HDAC and induces apoptosis in selected solid and hematologic neoplasia. This review critically analyzes the available literature on the therapeutic role of VPA on different types of cancer.