Glioblastoma (GBM) is the most frequent and invasive tumor of the central nervous system. Maximal surgical resection followed by radiotherapy with concomitant and adjuvant chemotherapy with temozolamide is the standard of care first-line treatment used for GBM. However, increased patient survival based on this first-line treatment is limited, and tumors invariably recur. At recurrence, most common treatment options are further surgical resection, conventional chemotherapy, or the use of the anti-vascular endothelial growth factor (VEGF) agent, bevacizumab. The tumor microenvironment (TME), which is composed of the extracellular matrix, interstitial fluid and stromal cells, including astrocytes, macrophages and endothelial cells, is a key regulator of GBM progression and therapeutic drug resistance. A peculiar feature of the TME in GBM is the blood-brain-barrier (BBB), a semipermeable membrane of endothelial cells connected by tight junctions, capable of preventing the passage of the majority of the pharmaceutical compounds to the GBM tumor. The TME is characterized by an immunosuppressive state with few tumor-infiltrating lymphocytes (TILs) and other cells activating the immune system. The comprehensive characterization of the molecular landscape of somatic genomic alterations of GBM has lead to the identification of a plethora of mutated genes as well as of abnormal rearrangements of several receptors including the epidermal growth factor receptor and platelet derived growth factor receptor α. This has allowed the introduction of novel therapies, including the use of tyrosine kinase inhibitors (TKIs). Moreover, the use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers, as well as encouraging results have been obtained that endorse the use of these antibodies in untreated brain metastases from malignant melanoma and from non-small cell lung cancer. Programmed cell death protein (PD-1) receptor/programmed death ligand 1 (PD-L1) inhibitors has been also proposed for GBM treatment. TME, mutational landscape and clonal evolution of GBM tumors are key factors of paramount importance for the efficacy of TKIs and ICIs used in the treatment of GBM. The current review summarizes the principal molecular and TME features of GBM providing the rationale for the use of TKIs and ICI immunotherapy. The main targeted therapies with TKIs and approaches using ICIs, that have been recently proposed, are also discussed.