Acute myeloid leukaemia has emerged as a paradigm for the concept of the cancer stem cell. This hypothesis presumes that the disease is maintained by a rare population of leukaemia-initiating stem cells which have acquired genetic or epigenetic changes. It is most likely that a single (epi)genetic event will not be sufficient to cause leukaemia, but that a number of sequential events are required. Similar to normal hematopoietic stem cells, both intrinsic as well as extrinsic factors that arise from the bone marrow niche, provide essential cues that regulate cell fate decisions such as leukaemic stem cell self-renewal and differentiation. This book reviews the genetic and epigenetic abnormalities that underlie the process of leukaemia transformation, and discusses which events potentially co-operate to induce leukaemia.