Glioblastoma is a multifaceted and therapeutically challenging disease. Despite decades of ground-breaking research work, therapeutic options for the cure of glioblastoma are limited. A substantial amount of knowledge has been added to the complicated web of intertwined protein networks related to glioblastoma. Researchers have dissected a wide variety of signaling cascades, which play fundamental role in disease onset, progression and drug resistance. Recent technological advancements have changed our understanding of the signal specificity and revealed that discrete spatio-temporal activation profiles of the same effectors resulted in diverse physiological responses. Detailed mechanistic insights revealed that deregulated oncogenic pathways played an instrumental role in onset and progression of glioblastoma. Genomic and proteomic studies have unraveled the molecular underpinnings of the TGF/SMAD pathway in glioblastoma. Overall, we hope that this review will enable researchers and clinicians to develop a better understanding of the underlying mechanisms of glioblastoma. Comprehensive interpretation of multi-omics data in glioblastoma will not only enrich our understanding of the heterogeneous nature of glioblastoma but also galvanize the development of personalized clinical approaches.