The efficacy of treating malignant gliomas with adjuvant therapies remains largely unsuccessful due to the inability to effectively target invading cells. Although our understanding of glioma oncogenesis has steadily improved, the molecular mechanisms that mediate glioma invasion are still poorly understood. It is clear that genetic alterations in malignant gliomas affect cell proliferation and cell cycle control, which are the targets of most chemotherapeutic agents. However, effective therapy against cell invasion has been less successful. Future treatment protocols must incorporate pharmacotherapeutic strategies that target resistant infiltrative glioma cells as well as proliferating ones. Thus, delineating the point of convergence of signaling pathways, which mediate glioma invasion, proliferation and apoptosis, may identify novel targets that can serve as possible points of therapeutic intervention. The optimization of novel strategies will require reliable preclinical testing using an in vivo animal model of brain invasion. Current applications of existing animal models are not currently optimized or characterized for use in glioma invasion research. As such, the development of a bona fide brain invasion model in vivo must be established. Progress in understanding molecular mechanisms driving glioma invasion will be critical to the success of managing and improving the outcome of patients with this grave disease.