A cancerous tumor in the brain known as glioblastoma multiforme (GBM) originates from astrocytes of the central nervous system. Consequently, GBM poses significant challenges to the oncology community because of its aggressive characteristics and poor prognosis. GBM hallmarks include fast growth, invasiveness, and high rates of recurrence. This tumor is highly heterogeneous with different genetic and molecular features found within the tumor cells. There is an ongoing obstacle to conceptualizing effective management for this grappling disease. This is largely due to the tumor displaying intra-heterogeneity, in addition to a plethora of differences in the tumor’s microenvironment. The heterogeneity exhibited by this tumor not only makes it more resistant to treatment but also influences its ability to evolve. The Epidermal Growth Factor Receptor (EGFR) which falls under the Human Epidermal Growth Factor (ErbB) family is a transmembrane receptor that assists in understanding complex molecular pathways involved in GBM formation. EGFR mutations have been shown to affect signaling cascades including Ras/Raf/MEK/ERK, PI3K/Akt/mTOR, JAK/STAT, PLC/PKC among others transforming cellular machinery involved in cell survival, proliferation and invasion. Knowledge about EGFR’s aberrant mutations can be useful for developing novel therapeutic strategies aimed at EGFR inhibition in GBM therapy. This gives hope for patients with this challenging disease to have better outcomes.