Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that can induce apoptosis when binding to either of two receptors bearing an intracellular death domain. The physiologic function of the TRAIL system, which also comprises three receptors not mediating a death signal has just begun to be elucidated. Expression of TRAIL, mostly upon stimulation by interferons, in different cytotoxic immune cells suggested it has a role as an important effector molecule in immune surveillance. In addition to its ability to induce apoptosis in transformed tumor cells, TRAIL has attracted attention for its possibly critical role in the defense against viral infection. Viruses may induce TRAIL expression in host and?or immune cells and sensitize host cells toward TRAIL-mediated apoptosis. On the other hand, viruses have evolved a variety of strategies to prevent TRAIL-mediated host cell death early in infection, which may contribute to allowing their replication and the spread of viral progeny. The knowledge of the molecular mechanisms leading to modification of TRAIL sensitivity in virus-host cell interactions may also impact upon future (virus-based) strategies to increase TRAIL sensitivity of tumor cells.