The NF1 tumor suppressor protein neurofibromin is a negative regulator of Ras. Neurofibromin is dynamically regulated by the proteasome, and its degradation and reexpression are essential for maintaining appropriate levels of Ras-GTP. Like p53, NF1/neurofibromin can be inactivated in cancer by both mutations and excessive proteasomal destruction; however, little is known about the mechanisms that underlie this latter process. Here, we show that a Cullin 3 (Cul3)/kelch repeat and BTB domain-containing 7 complex controls both the regulated proteasomal degradation of neurofibromin and the pathogenic destabilization of neurofibromin in glioblastomas. Importantly, RNAi-mediated Cul3 ablation and a dominant-negative Cul3 directly stabilize neurofibromin, suppress Ras and extracellular signal-regulated kinase, and inhibit proliferation in an NF1-dependent manner. Moreover, in glioblastomas where neurofibromin is chronically destabilized, Cul3 inhibition restabilizes the protein and suppresses tumor development. Collectively, these studies show a previously unrecognized role for Cul3 in regulating Ras and provide a molecular framework that can be exploited to develop potential cancer therapies.