Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. The current standard of care includes surgery, radiation therapy, temozolomide; and tumor‑treating fields leads to dismal overall survival. There are far limited treatments upon recurrence. Therapies to date are ineffective as a result of several factors, including the presence of the blood‑brain barrier, blood tumor barrier, glioma stem‑like cells and genetic heterogeneity in GBM. In the present review, the potential mechanisms that lead to treatment resistance in GBM and the measures which have been taken so far to attempt to overcome the resistance were discussed. The complex biology of GBM and lack of comprehensive understanding of the development of therapeutic resistance in GBM demands discovery of novel antigens that are targetable and provide effective therapeutic strategies.