The Notch pathway plays a key role in several processes including stem-cell self-renewal, proliferation, and cell differentiation. Several studies identified recurrent mutations in hematological malignancies making Notch one of the most desirable target in leukemia and lymphoma. The Notch signaling mediates resistance to therapy and controls cancer stem cells supporting the development of on-target therapeutic strategies to improve patients’ outcome. In this brief review, we outline the therapeutic potential of targeting Notch pathway in T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma.