Myelodysplastic syndromes (MDS) are a group of diseases of hematopoietic stem cells (HSCs) that occur primarily in the aging population. Allogeneic stem cell transplantation is the only curative treatment, but has marked limitations in most MDS patients. The standard-of-care, which focuses on hypomethylating agents (HMAs), invariably results in resistance and disease progression. Thus, there is a dire need for the development of new therapeutic approaches, but this is constrained by the lack of a clear understanding of the molecular pathobiology which underlies MDS. Recently, we have performed informatics analyses of primary MDS samples which demonstrate that a subset of patients have downregulation of genes, including SDHA, SDHB, and SDHD, that encode subunits and assembly factors of mitochondrial complex II (also known as succinate dehydrogenase: SDH). We confirmed this finding in hematopoietic stem and progenitor cells (HSPCs) of several genetically-distinct mouse models of MDS. Notably, downregulation of SDH results in suppression of the mitochondrial Krebs cycle and oxidative phosphorylation. The metabolic sequelae include an accumulation of Krebs cycle intermediate metabolites, which could act as antagonists to competitively inhibit the activity of various α-KG– dependent dioxygenases (2OGDDs). Collectively, these observations suggest that SDH dysregulation and/or downstream inhibition of 2OGDDs may drive MDS. Importantly, the downstream effect of these changes appears to be reminiscent of mutant isocitrate dehydrogenases (IDHs) and a non-canonical function of lactate dehydrogenase (LDH), which produce the oncometabolites R- or S-2-hydroxyglutarate (R/S-2HG) to competitively inhibit the activity of various 2OGDDs. Potentially related to our findings of downregulation of SDH genes in MDS, the IDH1/2 genes are often mutated, and that serum LDH levels have prognostic importance for survival in MDS and AML . Although mutations of SDH genes have not yet been reported in MDS and AML, they are frequently mutated in various other types of cancer. Strikingly, we observed that HMAs induce re-expression of SDH proteins in MDS HSPCs, especially SDHD and SDHAF2. Additionally, overexpression of Sdhd in MDS HSPCs restores their ability to differentiate and HMA treatment enhances these effects. We therefore hypothesize that SDH downregulation is a key molecular mechanism underlying the pathobiology of a subset of cases of myelodysplastic syndrome (MDS) and that SDH is a novel therapeutic target of DNA hypomethylating agents (HMAs). Dissecting the role of SDH in MDS should improve diagnosis, pathobiology, and targeted therapy for MDS, and potentially provide a new molecular metric for successful HMA therapy of MDS.