TRAIL is a member of the tumor necrosis factor (TNF) superfamily. TRAIL has drawn a lasting attention because of its selectivity and efficacy in inducing apoptosis in a variety of cancer cells but not in normal cells. The structures of both TRAIL and the protein in complex with the extracellular domain of death receptor 5 (sDR5) were elucidated. Because each factor of the ligand family and the receptor family is large, it poses an intriguing question of how recognition between cognate ligands and receptors is achieved in a highly specific manner without cross interactions. This review focuses on the unique properties of TRAIL and molecular strategies for the specific recognition between the two family members primarily based on the crystal structures of TRAIL and the TRAIL:sDR5 complex.