One of the major goals of researchers in the field of apoptosis is to understand the molecular mechanisms of the various components of the apoptotic pathways, with the hope to identify targets for novel cancer therapies. The discovery of a TNF-related, apoptosis-inducing ligand, TRAIL, that kills transformed cells with great specificity in vitro, has provided the hope that TRAIL may be used to induce cell death in tumor cells without affecting normal tissues. However, TRAIL signaling is very complex and a clear understanding of its function is necessary before it can be used in cancer therapy. Complexity of TRAIL-induced signaling is apparent from its ubiquitous expression, its ability to interact with five receptors, and its tumor-selective induction of apoptosis. The signaling events that mediate the tumor selectivity of TRAIL-induced apoptosis and the biological functions of each of the TRAIL receptors are not well characterized. This review will focus on the complexity of TRAIL and the role of c-FLIP in mediating TRAIL function.