Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo1L is a death ligand, a cytokine that activates apoptosis through cell surface death receptors. TRAIL is thought to be important in host tumor surveillance and metastasis suppression, and various therapeutic agonists that activate TRAIL receptors to induce tumor cell apoptosis are in clinical development. This review discusses recent findings about TRAIL pathway signaling and relates the signaling mechanisms to issues that need to be considered as we try to manipulate TRAIL signaling to treat cancer.