Acute myeloid leukemia (AML) is a common and deadly form of leukemia. New therapies are desperately needed. The availability of appropriate disease model systems is crucial to development of effective treatment. A significant progress in generating and characterizing such model systems has been made in the past decade. Here, the relative benefits of cell lines, transgenic mice and xenografted primary AML model will be compared, along with speculation on new models suitable for AML drug discovery.