Encouragingly, some types of cancer can now be considered treatable, with patients reasonably expecting their disease to be cured. Chemotherapy and radiation therapy are effective against these cancers because they activate the so-called intrinsic apoptosis pathways within the cancer cells. Unfortunately currently available treatments are only effective against a subset of tumor types. In contrast, other cancers, such as malignant glioma, typically do not respond to currently available therapies. Some of this resistance can be attributed to these tumor cells failing to undergo apoptosis upon anticancer treatment. Recently, considerable research attention has focused on triggering apoptosis in chemotherapy- and radiation-therapy-resistant cancer cells via an alternative route-the "extrinsic" pathway, as a means of bypassing this block in apoptosis. Binding of members of the tumor necrosis factor-alpha (TNF-alpha) family of death ligands to their receptors on the cell surface triggers this pathway. Death ligands can kill some cancer cells that are resistant to the apoptotic pathway triggered by conventional anticancer treatments. Some death ligands, such as TNF-alpha and FasL, cause unacceptable toxicity to normal cells and are therefore not suitable anticancer agents. However another death ligand, TNF-related apoptosis-inducing ligand (TRAIL)/Apo-2L, and antibodies that emulate its actions, show greater promise as candidate anticancer drugs because they have negligible effects on normal cells. This review will discuss the ability of TRAIL to induce apoptosis in malignant glioma cells and the potential clinical applications of TRAIL-based agents for glioma treatment.