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Notch signaling is known to differentially affect the development of lymphoid B and T cell lin-eages, but it remains unclear whether such effects are specifically dependent on distinct Notch ligands. Using a cell coculture assay we observed that the Notch ligand Delta-1 completely in-hibits the differentiation of human hematopoietic progenitors into the B cell lineage while pro-moting the emergence of cells with a phenotype of T cell/natural killer (NK) precursors. In contrast, Jagged-1 did not disturb either B or T cell/NK development. Furthermore, cells cul-tured in the presence of either Delta-1 or Jagged-1 can acquire a phenotype of NK cells, and Delta-1, but not Jagged-1, permits the emergence of a de novo cell population coexpressing CD4 and CD8. Our results thus indicate that distinct Notch ligands can mediate differential ef-fects of Notch signaling and provide a useful system to further address cell-fate decision pro-cesses in lymphopoiesis