Abstract Glioblastoma multiforme (GBM) is the most common brain tumor and has the worst prognosis. Several signaling molecules have been clearly implicated in the development, progression, and aggressiveness of GBM. Here we review the role of signal transducer and activator of transcription-3 (Stat3) in GBM. We particularly focus on its expression in clinical GBM samples, its role in brain tumorigenicity in cell lines and animal models, and discuss possible therapeutic strategies targeting Stat3. This review also summarizes the current knowledge regarding the role of Stat3 regulation by upstream activators and repressors in promoting GBM progression in both translational and clinical studies.