Acute myeloid leukemia (AML) is the most common type of leukemia in adults and approximately 13,000 new cases is diagnosed in the United States each year. Despite considerable improvement of survival rates for patients with leukemia over the past 50 years, the overall five-year relative survival rate for AML patients is only approximately 20%. Using a genetic mouse model of a common chromosome aberration, inv(16), found in AML patients, we have shown that leukemia arises as a result of a multi-step transformation process involving mutations that disrupt hematopoietic differentiation, and those that deregulate proliferation and self-renewal programs. Our research efforts are directed towards understanding the functional mediators and molecular pathways regulating normal hematopoisis and those underlying leukemia transformation. Leukemia stem cells (LSCs) are now recognized as the critical “seeds” of leukemia, and represent a fundamental challenge for leukemia therapy due to the inability to eradicate them through conventional treatments. Our long-term goal is to elucidate the molecular mechanism(s) regulating the maintenance of LSCs, to understand how they differ from normal hematopoietic stem cells, and to develop novel targeted therapeutics against LSCs. Our approach involves utilizing genetic mouse models as well as clinically relevant humanized models for translational studies.