The important role of the death effector domain of FADD prompted a search for interaction partners, the rationale being that those proteins would most likely constitute the adjacent downstream component of death signaling. In parallel, bioinformatic screens were used to search for additional proteins harboring regions with similarity to the DED. Those proteins would be candidates for addi tional death effectors, maybe working in the context of other death receptors. The experimental approach was faster and yielded results that fitted both bills: By using a yeast two-hybrid screen, a DED-interacting protein with a very interesting domain structure was identified (Boldin et al, 1996; Muzio e ta i, 1996). The iden tified protein, originally called Mach or FLICE, is now known as caspase-8. It was immediately clear that caspase-8 was a component of apoptosis signaling, since related caspases, particularly caspase-3, were already known to have a central role in this process (Cohen, 1997; Salvesen and Dixit, 1997). Interestingly, the N-terminus of caspase-8 carried two copies of a tandem repeat, a strong resemblance to the death effector domain of FADD. This finding established the death effector domain also as a homology domain. The fact that this region was identified as the active FADD interactor suggested that the death effector domain is able to mediate the interaction with other death effector domains, in a manner similar to that of the death domain.