To date six bona fide death receptors (DRs) have been discovered and include tumor necrosis factor receptor 1 (TNF-R1), Fas, DR3, DR4, DR5 and DR6. Each receptor contains an extracellular region and an intracellular region; the intracellular region harbors a death domain that is critical for transduction of apoptotic signals. These death receptors are activated by their respective ligands. For example, TNFalpha activates TNF-R1 while FasL and TL1A activate Fas and DR3 respectively. TNF-related apoptosis inducing ligand (TRAIL), also known as Apo2L, activates DR4 and DR5. The ligand for DR6 has yet to be identified. These death receptors are also believed to be activated in a ligand-independent manner. A large body of recent evidence suggests that death receptors could be utilized as key molecular targets to develop novel therapeutics. This review discusses the pros and cons of targeting death receptors in the development of novel cancer therapeutic agents.