Mitochondria are involved in hematopoietic cell homeostasis through multiple ways such as oxidative phosphorylation, various metabolic processes and the release of cytochrome c in the cytosol to trigger caspase activation and cell death. In erythroid cells, the mitochondrial steps in heme synthesis, iron (Fe) metabolism and Fe-sulfur (Fe-S) cluster biogenesis are of particular importance. Mutations in the specific delta-aminolevulinic acid synthase (ALAS) 2 isoform that catalyses the first and rate-limiting step in heme synthesis pathway in the mitochondrial matrix, lead to ineffective erythropoiesis that characterizes X-linked sideroblastic anemia (XLSA), the most common inherited sideroblastic anemia. Mutations in the adenosine triphosphate-binding cassette protein ABCB7, identified in XLSA with ataxia (XLSA-A), disrupt the maturation of cytosolic (Fe-S) clusters, leading to mitochondrial Fe accumulation. In addition, large deletions in mitochondrial DNA, whose integrity depends on a specific DNA polymerase, are the hallmark of Pearson's syndrome, a rare congenital disorder with sideroblastic anemia. In acquired myelodysplastic syndromes at early stage, exacerbation of physiological pathways involving caspases and the mitochondria in erythroid differentiation leads to abnormal activation of a mitochondria-mediated apoptotic cell death pathway. In contrast, oncogenesis-associated changes at the mitochondrial level can alter the apoptotic response of transformed hematopoietic cells to chemotherapeutic agents. Recent findings in mitochondria metabolism and functions open new perspectives in treating hematopoietic cell diseases, for example various compounds currently developed to trigger tumor cell death by directly targeting the mitochondria could prove efficient as either cytotoxic drugs or chemosensitizing agents in treating hematological malignancies.