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Glioblastoma (GBM) is the most malignant brain tumor, characterized with a rapid progression and poor prognosis despite modern therapies. Receptor tyrosine kinase (RTK) is a membrane tyrosine kinase that could be activated by binding ligands with the extracellular domain, and communicating signals according to the tyrosine kinase activity of the intracellular domain. Recent studies revealed that RTKs such as EGFR, PDGFR and MET play key roles in cancer progression through regulation of abundant cellular processes. As transmembrane proteins, RTKs work as a mediator between the extracellular environment and intracellular compartments, translating the tumor microenvironment (TME) signals into the tumor cells. TME is also a critical regulator for the malignant process, lately receiving considerable attention. It is composed of extracellular matrix (ECM), the stromal cells (i.e., endothelial cells, microglia and fibroblasts), secreted factors, and hypoxia environment, etc. Among these, the strong invasion and sustained angiogenesis of GBM are closely related to ECM-receptor interaction and -associated signaling events. In this chapter, we consider the interaction and mechanisms of RTKs and TME in GBM progression, especially the role of ECM-receptor mediated signaling in tumor invasion, hypoxia and angiogenesis, glioma stem cells and tumor metabolism. We then summarize and discuss recent improvements on the approaches of targeting RTK and TME as the therapy in the primary GBM.