Malignant peripheral nerve sheath tumors (MPNSTs), often found associated with neurofibromatosis type 1 (NF1), are aggressive tumors that pose significant diagnostic and therapeutic challenges. About 10% of NF1 patients may develop an MPNST, exhibiting a poor prognosis. With no effective treatment available, radical surgery and chemo- and radiotherapy are required to reduce tumor recurrence, metastasis and prolong patient survival. MPNST pathogenesis is poorly understood due mainly to its complex histopathology, but biallelic NF1 gene inactivation is essential for tumor development. There is also no defined molecular signature for MPNST development, although several cell-cycle and signalling regulation genes (CDKN2A, TP53, RB1, EGFR, CD44, PDGFR, PDGFRA, HGF, MET and SOX9) are deregulated. Constitutive activation of several critical cell signalling cascades also occurs in MPNSTs and these may define therapeutic targets. Both preclinical and clinical trials are proposed, most involving a combinatorial therapeutic approach. Multidisciplinary collaborative efforts are clearly essential to fully decipher both the complex molecular basis of MPNST development and to define potential therapeutic targets.