Leukemia stem cells (LSC) reside within a hierarchy of malignant hematopoiesis and possess the ability to instigate, maintain and serially propagate leukemia in vivo, while retaining the capacity to differentiate into committed progeny that lack these properties. In most cases, LSC appear to share immunophenotypic characteristics with committed hematopoietic progenitors, however have pathologically enhanced self-renewal, mediated through the activation of certain cellular pathways. The presence of a LSC that solely possesses the ability to initiate and sustain leukemia has implications for the treatment of patients with this disease. In this review, we will discuss these issues as well as some of the recent controversies regarding LSC frequency and alternative theories of leukemogenesis.