Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and β-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target. Display omitted ► CXCR4 and CXCL12 expression is elevated in murine and human MPNST cells and tumors ► CXCR4 depletion inhibits MPNST proliferation by downregulating cyclin D1 ► CXCR4 promotes tumorigenesis through the AKT/b-catenin signaling pathways ► Pharmacologic inhibition of CXCR4 blocks allograft and spontaneous tumor formation The expression of the chemokine receptor CXCR4 and its ligand CXCL12 is elevated in murine and human malignant peripheral nerve sheath tumors, which arise in a subset of patients with neurofibromatosis type 1. Inhibition of CXCR4 blocks the proliferation of these aggressive and often fatal tumors, suggesting CXCR4 as a potential therapeutic target.