TRAIL and agonistic antibodies raised against TRAIL death receptors are highly promising new anticancer agents. In this brief review, we describe the recent advances in the molecular understanding of TRAIL signaling and the progress made in using TRAIL or agonistic antibodies clinically in mono- and combination therapies. Synergies have been reported in various scenarios of TRAIL-based multidrug treatments, and these can be used to potentiate the efficacy of therapies targeting TRAIL death receptors. We pay particular attention to structure the current knowledge on the diverse molecular mechanisms that are thought to give rise to these synergies and describe how different signaling features evoking synergies can be associated with distinct classes of drugs used in TRAIL-based combination treatments.