TRAIL-R3 is a decoy receptor for TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), a member of the tumor necrosis factor (TNF) ligand family. TRAIL induces apoptosis in a broad range of cancer cell lines, but not in many normal cells-a finding that generated extraordinary excitement about its potential as a specific antitumor agent. In several cell types, decoy receptors inhibit TRAIL-induced apoptosis by binding to it and preventing its binding to TRAIL proapoptotic or death receptors. However, recently published data regarding the role of these receptors in TRAIL-induced cellular death are contradictory. The key to resolving this controversy may lie in the regulation and cellular localization of TRAIL receptors. In this regard, cloning and analysis of the TRAIL-R3 promoter will help to identify the cellular factors that regulate its transcriptional expression. This chapter summarizes current knowledge in this field and outlines directions for future research.