Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, highly metastatic, poor prognosis tumors for which effective therapeutic strategies are currently lacking. We summarize recent work focusing on preclinical evaluation of histone deacetylase inhibitors (HDACis) for the treatment of MPNST. HDACis are a novel drug class with anti-cancer therapeutic promise. Using human MPNST cell lines and xenograft models we found that a MPNST subset is highly sensitive to HDACis, whereas a fraction is relatively resistant. HDACis were found to induce autophagy in all MPNST cells in vitro and in vivo; in "sensitive" MPNST cells autophagy occurs in concert with apoptosis, whereas unopposed autophagy develops in "resistant" cells. Genetic and chemical autophagy blockade significantly enhances HDACi-induced apoptotic cell death in both resistant and sensitive cells. Combined chloroquine and HDACi treatment abrogates growth of human MPNST xenografts and lung metastases. The potential role of autophagy in cancer therapeutic response remains controversial; however, our study supports HDACi-induced autophagy as a MPNST survival mechanism. These data also imply that the consequences of drug-induced autophagy may be compound-type, tumor-type, or even molecular context-dependent, suggesting a complex crosstalk between autophagy and apoptosis. Clinical trials evaluating HDACis with autophagy blockade for therapy of MPNST therefore merit consideration.