The NF1 tumor suppressor gene encodes neurofibromin, a GTPase-activating protein (GAP) for p21^ras (Ras). Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML). Some heterozygous Nf1 mutant mice develop a similar myeloproliferative disorder (MPD), and adoptive transfer of Nf1-deficient fetal liver cells consistently induces this MPD. Human JMML and murine Nf1-deficient cells are hypersensitive to granulocyte-macrophage colony–stimulating factor (GM-CSF) in methylcellulose cultures. We generated hematopoietic cells deficient in both Nf1 and Gmcsf to test whether GM-CSF is required to drive excessive proliferation of Nf1^−/− cells in vivo. Here we show that GM-CSF plays a central role in establishing and maintaining the MPD and that recipients engrafted with Nf1^−/−Gmcsf^−/− hematopoietic cells are hypersensitive to exogenous GM-CSF.