Glioblastoma multiforme (GBM) is the common term for most gliomas given a CNS WHO Grade IV rating (Brennan et al., 2009, Ghosh et al., 2018, Louis et al., 2021, Paolillo et al., 2018, Shergalis et al., 2018, Szopa et al., 2017). It is the most frequently occurring malignant central nervous system tumor. The global incidence of GBM is 5.26 per 100,000 people (Omuro & DeAngelis, 2013), and it accounts for 14% of all primary brain tumors (Faris, 2022). It has a poor prognosis, with a 5-year survival rate of<5% after diagnosis (Tan et al., 2020, Verhaak et al., 2010). The poor prognosis and high mortality of GBM may be attributed to its complex pathogenesis, which in turn is governed by various cellular signaling pathways. This chapter will summarize different cell signaling pathways of GBM pathogenesis based on the disease prognosis and describe its clinical management through several preclinical models and clinical trials.