Caspase-8 belongs to the caspase family of proteases and plays a key role in the regulation of programmed cell death (apoptosis) during normal development as well as in adult life. Since signaling via the death receptor (extrinsic) pathway critically depends on caspase-8, the disturbance of caspase-8 expression or function may contribute to human diseases. For example, caspase-8 is inactivated in a variety of human cancers, which may promote tumor progression as well as resistance to current treatment approaches. Therefore, caspase-8 presents a promising target to restore defective apoptosis programs in cancers in order to overcome resistance.