The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity in normal cells. However, most cancers, including glioblastoma multiforme (GBM), display TRAIL resistance, hindering its application in clinical practice. Recent studies have unraveled novel mechanisms in regulating TRAIL-induced apoptosis in GBM and sought effective combinatorial modalities to sensitize GBM to TRAIL treatment, establishing pre-clinical foundations and the reasonable expectation that the TRAIL/TRAIL death receptor axis could be harnessed to treat GBM. In this review, we will revisit the status quo of the mechanisms of TRAIL resistance and emerging strategies for sensitizing GBM to TRAIL-induced apoptosis and also discuss opportunities of TRAIL-based combinatorial therapies in future clinical use for GBM treatment.