The marked heterogeneity in glioblastoma (GBM) may be induced through dynamic differentiation and dedifferentiation process of glioma cells. The hypothesis that environmental stimuli induce these phenotypic changes, including dedifferentiation into the stem cell phenotype which contributes to the high invasiveness and resultant poor outcome in GBM patients, is recently being proven. In the process of cancer invasion and metastasis, the phenotypic change has also been described as epithelial-mesenchymal transition (EMT). This biological process is mainly dependent on hypoxic stimuli and also on transforming growth factor-β (TGF-β) released from glioma stem cells, mesenchymal stem cells, and myeloid cells recruited by hypoxia. The tumor microenvironment, especially hypoxia, inducing such dynamic phenotypic changes can be a good therapeutic target in the treatment of GBM.