Mechanistic/mammalian target protein of rapamycin (mTOR) is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants such as nutrient availability, energy sufficiency, stress, and growth factor concentration. mTOR participates in two complexes, designated mTOR complex 1 (mTORC1) and 2 (mTORC2), both of which phosphorylate multiple substrates. Recent studies have revealed that the fine-tuning activity of mTOR complexes contributes to both maintenance of hematopoietic stem cells (HSCs) and suppression of leukemogenesis. Dysregulation of mTORC1 activity results in impaired HSC homeostasis. Abnormalities of mTOR signaling are observed in many patients with leukemia and genetic studies clearly show that the leukemogenesis associated with Pten deficiency involves both mTORC1 and mTORC2. Although the several mTOR inhibitors have been developed for cancer therapy, effectiveness of the inhibitors for eradication of leukemia stem cells (LSCs) is unknown. Advances in understanding of how mTOR signaling is involved in mechanisms of normal HSC and LSC homeostasis may lead to novel therapeutic approaches that can successfully eradicate leukemia.