The natural occurring tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis following binding to the two TRAIL death receptors (DRs). Its recombinant form and monoclonal antibodies against the TRAIL DRs induce cell death in a wide variety of tumor cell lines and xenografts without causing toxicity to normal cells and are therefore potential attractive anticancer agents. These agents are currently in early clinical development. The phase 1 and 2 studies showed until now limited toxicity and tumor responses have been observed. Ongoing studies focus especially on combination of these agents with other targeted therapies or cytotoxic therapies. In this review, we summarize current knowledge on these agents and highlight their potential role in the intrinsically chemotherapy-resistant glioblastomas. In addition, we discuss the mechanisms to sensitize tumors cells to rhTRAIL by combination with the proteasome inhibitor bortezomib.