Glioblastoma multiformes (GBMs) are extensively heterogeneous at both cellular and molecular levels. Current therapeutic strategies include targeting of key signaling molecules using pharmacological inhibitors in combination with genotoxic agents such as temozolomide. In spite of all efforts, the prognosis of glioma patients remains dismal. Therefore, a proper understanding of individual molecular pathways responsible for the progression of GBM is necessary. The epidermal growth factor receptor (EGFR) pathway is probably the most significant signaling pathway clinically implicated in glioma. Not surprisingly, anti-EGFR therapies mostly prevail for therapeutic purposes. The Wnt/β-catenin pathway is well implicated in multiple tumors; however, its role in glioma has only recently started to emerge. We give a concise account of the current understanding of the role of both these pathways in glioma. Last, taking evidences from a limited literature, we outline a number of points where these pathways intersect each other and put forward the possibility of combinatorially targeting them for treatment of glioma.