Glioblastoma (GBM), a highly malignant brain tumor of adults and children, diffusely invades within the non-neoplastic brain. Despite aggressive current therapeutic interventions, improved therapeutic strategies are greatly needed. Interactions between the tumor and constituents of its microenvironment are known to regulate malignancy, and heparan sulfate proteoglycans (HSPGs) are important as they bind diverse extracellular proteins, including growth factors and cell adhesion molecules, regulating the activity of several ligand-mediated signaling pathways. Recent work from our group described a mechanism by which GBM regulates PDGFR-alpha signaling via enzymatic alteration of heparan sulfate proteoglycans (HSPGs) in the extracellular microenvironment. Blocking tumor-induced alterations of HSPGs, which can be achieved by pharmacological strategies, would potentially inhibit multiple oncogenic signaling pathways in tumor cells and disrupt critical tumormicroenvironment interactions. Here we examine HSPGs and the enzymes that modify them in GBM. We compare their expression across tumor subtypes, their potential roles in oncogenesis, and their potential as novel therapeutic targets in GBM.