Juvenile myelomonocytic leukemia (JMML) is a rare, clonal, mixed myeloproliferative and myelodysplastic disorder afflicting young children. Patients with JMML respond poorly to most standard chemotherapy regimens and, whereas stem cell transplantation is the only known curative approach, even this modality is hampered by high relapse rates. The pathogenesis of JMML arises from dysregulation of signal transduction through the Ras pathway. This dysregulation results in JMML cells demonstrating selective hypersensitivity in vitro to granulocyte macrophage colony-stimulating factor (GM-CSF). Potential causative mutations or other genetic abnormalities in three genes (eg, RAS, neurofibromatosis type 1, and PTPN11), all of which are positioned in the GM-CSF/Ras signal transduction pathway, account for up to 75% of cases of JMML. These pathogenetic advances are paving the way for the development and testing of mechanism-based molecularly targeted therapeutics in JMML aimed specifically at the GM-CSF signal transduction pathway through Ras.