A central question in cancer biology is whether malignancy arises in self-renewing tissue stem cells that suffer oncogene activation or in differentiated cells that acquire properties of unremitting self-renewal? In two papers, Weissman and colleagues document both mechanisms: chronic leukemia arising by mutation affecting the hematopoietic stem cell (HSC) and acute leukemia evolving from committed granulocyte-macrophage progenitors that have acquired the self-renewal machinery of HSCs.