Leukemia results from the uncontrolled accumulation of primitive, poorly differentiated blood cells, and is a consequence of the accumulation of mutations in hematopoietic precursor cells. These mutations include point mutations (single base pair insertions, deletions, or substitutions), gross chromosomal rearrangements such as deletions, insertions, amplifications, and translocations, and epigenetic changes. It seems likely that mutations affecting at least two pathways are required for the development of leukemia. One of these pathways regulates cell accumulation; the second regulates hematopoietic differentiation. Molecularly targeted therapy, which interrupts functions of the leukemogenic proteins generated by mutations, has been developed and shown to be effective for several forms of malignancy. Therefore, it is our hope and belief that a clearer understanding of the mechanism(s) that underlie leukemic transformation will lead to effective new therapies for this dreaded disease.