Acute leukemia is an aggressive form of hematological malignancy, which is characterized and classified into different subtypes according to the morphology and immunophenotype of the leukemic blasts. However in the past decade, it became clear that it is the genetic makeup and probably the origin of leukemic stem cells, which determine the phenotype, aggressiveness, and prognosis of the disease. To further advance our knowledge, various molecular and cellular methodologies have been developed by clinical and basic researchers to not only identify and monitor these genetic changes in patients, but also model and dissect the underlying transformation mechanisms of the disease. In this chapter, I will summarize some of the key developments and latest technologies that have been instrumental to modern leukemia research.