No effective systemic treatment exists for malignant peripheral nerve sheath tumors (MPNSTs). These tumors have been reported to show increased activity in the mitogen-activated protein kinase pathway from the loss of neurofibromatosis-1 regulation and occasionally from BRAF V600E mutation. A patient with sporadic metastatic MPNST and the BRAF V600E mutation was treated with standard doses of sorafenib and later vemurafenib and followed for response. The patient showed a rapid but modest and transient response to sorafenib and a very dramatic response to vemurafenib. This case represents the first report of successful systemic treatment of MPNST with an inhibitor of the BRAF V600E mutation. It will be important to define the general utility of this approach and related therapies in this disease.