Mutations in transcription factors (TFs) and protein tyrosine kinases (PTKs), which result in inhibition of differentiation/apoptosis or enhanced proliferative/survival advantage of hematopoietic stem/progenitor cells, are two classes of the most frequently detected genetic abnormalities in leukemias. The critical roles for mutant TFs and/or PTKs to play in leukemogenesis, and the absence of mutant TFs/PTKs in normal hematopoietic cells, suggest that the two types of aberrant molecules may serve as ideal therapeutic targets. The great success of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in treating acute promyelocytic leukemia through modulation of the causative PML-RARalpha oncoprotein represents the first two paradigms of mutant TFs-targeting therapeutic strategies for leukemia. More recently, tyrosine kinase inhibitor STI-571/Imatinib mesylate/Gleevec in the treatment of Breakpoint Cluster Region-Abelson (BCR-ABL) positive leukemia elicits paradigm of mutant PTKs as ideal antileukemia targets. Thus to further improve clinical outcome of leukemia patients, elucidation of pathogenesis of leukemia, screening for oncoprotein-targeting small molecules, as well as rationally designed combination of drugs with potential synergy are of importance.