Glioblastoma (GBM) is an extremely aggressive tumor of the central nervous system, with a prognosis of 12–15 months and just 3–5% of survival over 5 years. This is mainly because most patients suffer recurrence after treatment that currently consists in maximal resection followed by radio- and chemotherapy with temozolomide. The recurrent tumor shows a more aggressive behavior due to a phenotypic shift toward the mesenchymal subtype. Proneural-mesenchymal transition (PMT) may represent for GBM the equivalent of epithelial–mesenchymal transition associated with other aggressive cancers. In this review we frame this process in the high degree of phenotypic inter- and intra-tumor heterogeneity of GBM, which exists in different subtypes, each one characterized by further phenotypic variability in its stem-cell compartment. Under the selective pressure of different treatment agents PMT is induced. The mechanisms involved, as well as the significance of such event in the acquisition of a multitherapy resistance phenotype, are taken in consideration for future perspectives in new anti-GBM therapeutic options.