CXCR4, a cell surface chemokine receptor, mediates cellular dissemination, invasion, and proliferation in a wide range of cancers including gliomas. It is over-expressed in glioma progenitor cells, and its protein ligand, CXCL12, has been shown to mediate a specific proliferative response in these cells thereby implicating a role for CXCR4 in glioma initiation and renewal. Given the failure of currently employed therapies to meaningfully impact prognosis in patients with high-grade gliomas, the CXCR4-CXCL12 axis represents a novel biologically relevant mechanism that could be specifically targeted for therapy. From this perspective, this review summarizes the biological effects of CXCR4 activity and its implications for glioma pathogenesis. Ultimately, the development of effective treatment approaches for malignant glioma must be based on a rational mechanistic understanding of tumor cell biology. As such, this article presents such a framework with regard to the CXCR4 pathway in glioma thereby supporting the further investigation of CXCR4 as a therapeutic target in patients with this disease.