We have exploited inherited predispositions as entry points for understanding mechanisms of hematopoietic growth control and to uncover genetic lesions that contribute to leukemogenesis. This work has converged on the Ras pathway. We discovered mutations in the NF1 and PTPN11 genes in juvenile myelomonocytic leukemia (JMML) and other myeloid malignancies. NF1, which encodes a GTPase activating protein for Ras, functions as a tumor suppressor gene. The PTPN11 gene encodes SHP-2, a non-receptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to Ras and other effectors. Somatic PTPN11 mutations exist in 35% of JMML samples that are predicted to activate phosphatase activity by disrupting the interaction between the N-SH2 and the PTP domains of SHP-2. In recent experiments, we harnessed the interferon-inducible Mx1-Cre recombinase to develop a tractable mouse models of myeloid malignancies inactivating Nf1 in hematopoietic cells. Based on our work in children with inherited predispositions, we hypothesized that an oncogenic RAS mutation could initiate myeloid leukemia, and recently showed that this was true in studies in which we induced the expression of a latent Kras oncogene in hematopoietic cells. The ability to temporally regulate Nf1 inactivation or Kras activation now enables us to examine the biochemical and cellular effects of hyperactive Ras in primary hematopoietic cells, including stem and progenitor populations. We have recently developed robust protocols that utilize flow cytometry to assay phopshorylated signaling molecules in primary hematopoietic cells. A long term, goal of these studies is to understand how oncogenic Ras alterns the architecture of signaling networks. We have also launched a major effort to exploit retroviral insertional mutagenesis to uncover genes that regulate hematopoietic cell fates and cooperate with hyperactive Ras to promote transformation from chronic to acute leukemia.