Notch receptors are transmembrane proteins critically determining cell fate and maintenance of progenitor cells in many developmental systems. Notch signaling is involved in stem cell self-renewal and regulates the main functions of cell life at different levels of development cell proliferation, differentiation and apoptosis. By virtue of its involvement in the regulation of cell physiology, it is not surprising that a deregulation of the Notch pathway leads to the development of different tumors. In this review, we critically discuss the latest findings concerning Notch roles in hematologic oncology, with a special focus on T-cell acute lymphoblastic leukemia and B-cell malignancies. We also describe the molecular mediators of Notch-driven oncogenic effects and the current pharmacological approaches targeting Notch signaling.