Glioblastoma multiforme (GBM) tumors are one of the most deadly forms of human cancer and despite improved treatments, median survival time for the majority of patients is a dismal 12-15 months. A hallmark of these aggressive tumors is their unique ability to diffusively infiltrate normal brain tissue. To understand this behavior and successfully target the mechanisms underlying tumor progression, it is crucial to develop robust experimental ex vivo disease models. This review discusses current two-dimensional (2D) experimental models, as well as animal-based models used to examine GBM cell migration, including their advantages and disadvantages. Recent attempts to develop three-dimensional (3D) tissue engineering-inspired models and their utility in unraveling the role of microenvironment on tumor cell behaviors are also highlighted. Further, the use of 3D models to bridge the gap between 2D and animal models is explored. Finally, the broad utility of such models in the context of brain cancer research is examined.