NOTCH1 is a well-validated target in hematopoietic malignancy, with NOTCH1 activating mutations identified in more than 50% of T-cell acute lymphoblastic leukemias. Moreover, a recent report has identified NOTCH1 activating mutations in 12% of chronic lymphocytic leukemias. While the frequency of NOTCH1 mutations and the well-documented role of this protein in the pathogenesis and maintenance of T-ALL support targeting NOTCH1 as a therapeutic strategy, the critical role of this protein in normal cell-fate specification and differentiation lead to complexities in its successful targeting. In this review, we will discuss potential approaches to targeting NOTCH1 in hematopoietic malignancies, including inhibition of the enzymes involved in its activation, antibodies directed against either the receptor or its ligands, and direct interference with the NOTCH1 transcriptional complex. Moreover, we will discuss the challenges to each of these approaches as well as potential solutions to overcoming these difficulties.