Most adult patients with acute myeloid leukemia (AML) die from their disease. Relapses are frequent even after aggressive multiagent chemotherapy and allogeneic stem cell transplantation. AML is a biologically heterogeneous disease, characterized by frequent cytogenetic abnormalities and an increasing spectrum of genetic mutations and molecular aberrations. Laboratory data suggest that AML originates from a rare population of cells, termed leukemic stem cells (LSCs) or leukemia-initiating cells, which are capable of self-renewal, proliferation and differentiation. These cells may persist after treatment and are probably responsible for disease relapse. This review will describe bench and translational research in LSCs and discuss how the data should be used to change the direction of developmental therapeutics and clinical trials in AML.