Glioblastoma (GBM) is the most common and fatal primary malignant tumor in the central nervous system. The main genetic alterations involved in GBM regard the PI3K/Atk and the MAPK pathways, which can be activated by the epidermal growth factor receptors (HER), and regulate cell cycle and apoptosis. Indeed, HER receptors overexpression in cancer is a poor prognostic marker and, therefore, is becoming a promising therapeutic target. However, the main obstacles to the delivery of drugs into the brain are the tumor microenvironment and the blood-brain barrier, which make selective targeting not trivial to achieve. In this scenario, polymeric nanoparticles functionalized with selective ligands are emerging as powerful vectors to reach into one of the most difficult organs in the human body.