Glioblastoma,IDHwild-type is the most common and aggressive form of glial tumors. The exact mechanisms of glioblastoma oncogenesis, including the identification of the glioma-initiating cell, are yet to be discovered. Recent studies have led to the hypothesis that glioblastoma arises from neural stem cells and glial precursor cells and that cell lineage constitutes a key determinant of the glioblastoma molecular subtype. These findings brought significant advancement to the comprehension of gliomagenesis. However, the cellular origin of glioblastoma with mesenchymal molecular features remains elusive. Mesenchymal stromal cells emerge as potential glioblastoma-initiating cells, especially with regard to the mesenchymal molecular subtype. These fibroblast-like cells, which derive from the neural crest and reside in the perivascular niche, may underlie gliomagenesis and exert pro-tumoral effects within the tumor microenvironment. This review synthesizes the potential roles of mesenchymal stromal cells in the context of glioblastoma and provides novel research avenues to better understand this lethal disease.