The myelodysplastic syndromes (MDS) are a heterogeneous group of neoplastic hematopoietic stem cell disorders characterized by peripheral blood cytopenias and a proclivity for transformation into acute leukemia. Allogeneic bone marrow transplant is the most effective therapy available, but carries high mortality and is a viable option only in younger patients with early disease. The presence of impaired cellular maturation in the setting of marrow hypercellularity has prompted the use of differentiation therapy in MDS. Agents that induce differentiation apparently by altering chromatin structure, such as DMA methyltransferase (Dmt) inhibitors and histone deacetylase (HDAC) inhibitors, are now in clinical trials for MDS as well as acute leukemias and other neoplasias, and recently the Dmt inhibitor 5-azacytidine has been approved by the FDA for MDS. However, many of the novel drugs currently being tested are associated with significant toxicity and in many cases require long term subcutaneous injection or IV infusion. We have found that valproic acid (VPA; depakote), a widely prescribed anticonvulsant, potently inhibits histone deacetylases (HDACs) at concentrations that are within the therapeutic range for treatment of epilepsy. In preclinical studies, we find that a therapeutic concentration of VPA causes robust hyperacetylation of core histones and induces differentiation of leukemic cell lines in culture, as assessed by increased expression of multiple molecular markers of differentiation. We also find that VPA robustly induces the expression of the cell cycle inhibitor p21, similar to other HDAC inhibitors. Furthermore, and in contrast to other HDAC inhibitors, VPA does not inhibit HDAC6, which functions in the cytoplasm to regulate microtubule polymerization, or HDAC10, suggesting a level of specificity in the inhibition of HDACs by VPA. Thus, we plan to administer VPA to patients with MDS to test whether VPA: (1) improves peripheral blood indices and reduces transfusion requirements, (2) inhibits HDACs in vivo, (3) abrogates the hematopoietic defect in the bone marrow or affects other objective markers of the disease, including a change in the size of the MDS clone. VPA offers the significant advantages that it is a clinically well-characterized, relatively safe medication that can be administered orally and can be accurately monitored by well-established methods.