The worldwide increasing incidence of skin-derived cancer and their diversity requires development of novel therapeutic strategies. The malignant melanoma, for example, is a highly aggressive cancer with the capacity to metastasize at early stages. Together with resistance to chemotherapeutic agents it results in overall poor prognosis of melanoma patients once metastasis has occurred. Death receptor-induced cell death may represent an innovative therapeutic approach for the specific elimination of skin tumor cells. Activation of death receptors leads to induction of several apoptotic and non-apoptotic signaling pathways, which are regulated in a complex manner by different proteins. In this context cIAP1 and cIAP2 were recently described to play a substantial role in resistance to extrinsic, in particular for TNF-induced, cell death. This study shows that cIAPs are essential to prevent CD95-mediated cell death. Loss of cIAPs caused by a chemical IAP antagonist leads to dramatic sensitization of skin tumor cells to CD95 ligand. The cell death mediated by CD95 and IAP antagonist is neither entirely caspase-dependent nor caspase-independent. Only a combination of caspase and RIP1 kinase inhibition is sufficient to block CD95-mediated cell death in absence of cIAPs. RIP1 is a known target of cIAP activity. Here it is demonstrated that cIAPs inhibit recruitment of RIP1 to the CD95 DISC and suppress formation of the secondary receptor-independent complex (complex II). In addition, loss of RIP1 protects cells from IAP angagonist-mediated sensitization to CD95L. These underline that RIP1 is a key regulator of CD95-initiated cell death pathways which is on its part regulated by cIAPs. cFLIP is a highly efficient anti-apoptotic protein and therefore also an important regulator of death receptor-mediated cell death. Increased cFLIP expression confers resistance of tumor cells to death ligands and promotes tumor progression. This study shows that cFLIP inhibits death receptor-mediated cell death by limiting activation of the pro-apoptotic molecule Caspase-8 at the DISC. Suppression of cFLIP causes increased Caspase-8 activation at the DISC and is therefore sufficient to sensitize cells to death ligands. Interestingly, it was revealed that cFLIP isoforms differentially contribute to resistance to CD95L in absence of cIAPs. Only cFLIP(L) and not cFLIP(S) interfere with RIP1 recruitment to the DISC and the subsequent formation of the complex II. This protects cFLIP(L), but not cFLIP(S), expressing cells from death ligand-induced cell death in absence of cIAPs. This study demonstrates a remarkable and previously unexpected specificity concerning the mechanism of death inhibition by cFLIP isoforms. These findings provide a new insight in the fundamental roles of cFLIP, cIAPs and RIP1 in regulation of death receptor signaling and may help to develop novel therapeutic approaches to overcome death ligand resistance of skin tumors.