TNF-related apoptosis-inducing ligand or TRAIL is a 281 amino acid cytokine that initiates apoptosis by binding to specific death receptors on the cell surface. Both full-length cell surface expressed TRAIL and picomolar concentrations of soluble TRAIL rapidly induce apoptosis in a wide variety of transformed cell lines of diverse origin. Serum TRAIL levels are significantly lower in patients with coronary artery disease than in normal patients. Plasma TRAIL levels are significantly higher in patients with HIV-1 than in normal patients and correlate positively with viral load. This protein has generated excitement as a potential tumor-specific cancer therapeutic because, as a stable soluble trimer, it selectively induces apoptosis in many transformed cells but not in normal cells. Transcriptional activation of Apo2L/TRAIL by interferons (IFNs) through specific regulatory elements in its promoter, and possibly by a number of other cytokines, reveals its possible involvement in the activation of natural killer cells, cytotoxic T lymphocytes, and dendritic cells.