Genetic loss of surface Fas antigen expression leads to reduced apoptosis of myeloid and lymphoid progenitor cells, and a propensity to develop autoimmunity and myeloid leukemia in mouse models. Oncogenic p21^ras decreases surface Fas antigen expression and renders fibroblasts resistant to Fas mediated apoptosis. Neurofibromin, which is encoded by NF1, is a GTPase activating protein that negatively regulates p21^ras activity. NF1 loss leads to deregulation of p21^ras-effector pathways, which control myeloid cell survival. Heterozygous inactivation of Nf1 increases mast cell numbers in Nf1 +/− mice, and enhances mast cell survival in response to c-kit ligand (kit-L). Here, we show that Nf1-deficient mast cells have reduced surface Fas antigen expression in response to kit-L and are resistant to Fas ligand-mediated apoptosis. Using genetic intercrosses between Nf1 +/− and class I _A-PI-3K-deficient mice, we demonstrate that hyperactivation of the p21^ras-class I_A PI-3K pathway is the mechanism for this phenotype. Finally, we demonstrate that mast cells from both Fas antigen-deficient mice and Nf1 +/− mice are resistant to apoptosis following kit-L withdrawal in vivo. Thus, therapies designed to decrease p21^ras activity and up-regulate Fas antigen expression may limit the pathological accumulation of myeloid cells in disease states where p21^ras is hyperactivated.