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The Notch pathway is a conserved signaling network that regulates many cellular processes including renewal of stem cells, differentiation of multiple cell lineages, proliferation and apoptosis.1 Notch signaling involves the binding of Notch ligands to Notch receptors followed by proteolytic cleavage events, translocation of intracellular Notch (ICN) to the nucleus and regulation of target genes via the interaction of transcription factor CSL/RBPJ and the MAML family of transcriptional co-activators.1, 2 The Notch pathway is involved in lymphoid development and recurrent activating mutations in NOTCH1 contribute to T lymphoblastic leukemias.3 Whether Notch signaling is actively involved in the regulation of myeloid development and myeloid leukemogenesis is less clear due to conflicting reports.4, 5, 6 In this study, we abrogated canonical Notch signaling throughout the hematopoietic system to evaluate the role of Notch in myelopoiesis and to conclusively determine if inhibition of Notch signaling can contribute to aberrant myelopoiesis and lead to the development of a myeloid neoplasm.