Smac-mimetic compounds are currently in cancer Phase I clinical trials. We have shown Smac-mimetics antagonize Inhibitor APoptosis proteins (IAPs) and induce TNF production leading to the death of a subset of cancerous and as well as primary cells. High concentrations of TNF are toxic therefore it is essential to understand how Smac-mimetics drive TNF production. We have shown that Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 induce directly TNF production when IAPs are depleted. Interestingly, we show that in addition to NF-κB signaling, the MAPK pathway is also involved in the regulation of TNF synthesis following IAPs inhibition. Our results suggest that IAPs limit spontaneous TNF expression by regulating RIPK1-mediated NF-κB and MAPK activities.