Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) has been reported to specifically induce malignant cell death being relatively nontoxic to normal cells. Since its identification 15 years ago, the antitumor activity and therapeutic value of TRAIL have been extensively studied. Five receptors quickly emerged, two of them being able to induce programmed cell death in tumor cells. This review takes a comprehensive look at this ligand and its receptors, and its potential role in primary bone tumors (osteosarcoma and Ewing's sarcoma) therapy. The main limit of clinical use of TRAIL being the innate or acquired resistance mechanisms, different possibilities to sensitize resistant cells are discussed in this review, together with the impact of bone microenvironment in the regulation of TRAIL activity.