Malate dehydrogenase, mitochondrial also known as malate dehydrogenase 2 is an enzyme that in humans is encoded by the MDH2 gene. Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the mitochondria and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. Mutations in the MDH2 gene have been associated with several cancers, including uterine cancer, prostate cancer, pheochromocytoma and other paragangliomas. In particular, MDH2 has been found to be overexpressed in doxorubicin-resistant uterine cancer cells and may contribute to drug resistance. Since MDH2 plays a major role in malate-aspartate shuttling in ATP production, its overexpression likely supplies additional energy for P-glycoprotein to pump chemotherapeutic drugs out of the cells. Likewise, MDH2 contributes to docetaxel resistance in prostate cancer cells via the JNK pathway, and its knockdown reduced ATP levels as well as increased drug sensitivity. Thus, MDH2 may be an effective therapeutic target to enhance drug treatments for cancer.