Leukemia is a group of heterozygous diseases of hematopoietic stem/progenitor cells that involves dynamic change in the genome. Dissection of genetic abnormalities critical to leukemia initiation provides insights into the elusive leukemogenesis, identifies distinct subsets of leukemia and predicts prognosis individually, and can also provide rational therapeutic targets for curative approaches. The past three decades have seen tremendous advances in the analysis of genotype-phenotype connection of leukemia, and in the identification of molecular biomarkers for leukemia subtypes. Intriguingly, differentiation therapy, targeted therapy and chemotherapy have turned several subtypes of leukemia from highly fatal to highly curable. The use of all-trans retinoic acid and arsenic trioxide, which trigger degradation of PML-RARalpha, the causative fusion protein generated by t (15;17) translocation in acute promyelocytic leukemia (APL), has led to a dramatic improvement of APL clinical outcome. Imatinib mesylate/ Gleevec/STI571, which inhibits the tyrosine kinase activity of BCR-ABL oncoprotein, has now become the new gold standard for the treatment of chronic myeloid leukemia. Optimal use of chemotherapeutic agents together with a stringent application of prognostic factors for risk-directed therapy in clinical trials has resulted in a steady improvement in the treatment outcome of acute lymphoblastic leukemia. Hence, the pace of progress extrapolates to a prediction of leukemia control in the twenty-first century.