Two broad classes of mutations are associated with acute leukemia. One class of mutations, exemplified by activating mutations in tyrosine kinases such as BCR/ABL, FLT3, TEL/PDGFBR, or oncogenic RAS mutations result in enhanced proliferative and survival advantage for cells. These mutations can be targeted by small molecule inhibitors of the respective tyrosine kinases or potentially by farnesyl transferase inhibitors. A second class of mutations is loss-of-function mutations in hematopoietic transcription factors, as exemplified by the acute myeloid leukemia 1 (AML1)/ETO or PML/RARα gene rearrangements, or point mutations in AML1 or C/EBPα. Treatment that targets this class of mutations can include agents that specifically induce differentiation and apoptosis of leukemic cells, as demonstrated by the use of ATRA in PML/RARα-positive acute promyelocytic leukemia and potentially by HDAC inhibitors. Finally, although not known to be mutant in leukemia, genes and pathways that are responsible for the self-renewal potential of leukemia stem cells, such as WNT, Notch, BMI-1, or HOX family members may also be candidates for molecularly targeted therapy.