Copyright © 2015 Wolters Kluwer Health, Inc. Purpose of review Recent studies have enhanced our understanding of the role of the SIRT1 deacetylase in regulation of normal hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), and its importance in regulating autophagy and epigenetic reprogramming in response to metabolic alterations. Recent findings Studies employing conditional deletion mouse models indicate an important role of SIRT1 in maintenance of adult HSCs under conditions of stress. SIRT1 is significantly overexpressed in LSC populations from acute myeloid leukemia (AML) patients with the FLT3-ITD mutation, and maintains their survival, growth and drug resistance, as previously described for chronic myelogenous leukemia (CML). SIRT1 can also enhance leukemia evolution and drug resistance by promoting genetic instability. Recent studies indicate an important role of SIRT1 in regulating autophagy in response to oxidative stress and nutrient requirements, and have elucidated complex mechanisms by which SIRT1 regulates epigenetic reprogramming of stem cells. Summary SIRT1 inhibition holds promise as a novel approach for ablation of LSCs in chronic phase CML or FLT3-ITDassociated AML. Additional studies to understand the role of SIRT1 in linking metabolic alterations to genomic stability, autophagy and epigenetic reprogramming of stem cells are warranted.