Glioblastoma Multiforme (GBM) is the most malignant primary brain tumor in adults. The current medical treatment is a combination of resection, followed by radiotherapy and chemotherapy, which results in a dismal survival of 14.6 months. Additionally, this treatment regimen is aggressive and poorly selective, resulting in intracranial metastases and systemic side effects. The main features of GBM involve nuclear atypia, highly infiltrative and invasive phenotype and necrosis. Moreover, the heterogeneous composition, characterized by the presence of distinct cell types with different morphologies, genetic mutation and differentiation stage, poses a challenge in the identification of the proper treatment strategy. The presence of a Cancer Stem Cells (CSCs) niche, combined with the heterogeneity of the tumor microenvironment, composed of immune cells, endothelial cells and other infiltrating cells, facilitates invasion, proliferation and angiogenesis.