Among central nervous system (CNS) diseases, glioblastoma (GBM) ranks first among the most aggressive primary tumors in adults and is associated with a high fatality rate globally. GBM is characterized by an infiltrative nature and high genetic heterogeneity, which make treatment very challenging. Today, the most common therapies are based on surgical resection, when possible, followed by radio-chemotherapy treatment; however, these procedures do not produce effective outcomes in the post-operative course due to the complex nature of the tumor, thus resulting into a high recurrence rate. Based on the previous considerations, further research is crucial to identify the mechanisms involved in the onset of this disease to achieve a more specific therapeutic response, as well as targeted therapies able to maximize the anti-cancer efficiency while minimizing potentially adverse effects on healthy tissues.