TNF-induced apoptosis is tightly regulated by the NF-κB pathway. Under physiologic conditions, TNFα stimulation induces NF-κB activation and cell survival, due to the regulation of anti-apoptotic genes, including c-FLIP, a caspase-8 inhibitor, whose expression is sufficient to protect cells against TNF-induced apoptosis. TNF triggers cell death only in circumstances where the NF-κB pathway is defective. Rushworth and collaborators have recently demonstrated, however, that the heme oxygenase-1 (HO-1), also known as Heat shock protein 32 (Hsp32) [1], like c-FLIP, can afford protection against TNF-induced cell death in AML cells, despite NF-κB inactivation [2]. They now provide evidence that TNF mediated HO-1 up-regulation, is negatively regulated by c-FLIP, revealing a novel negative regulatory feedback loop controlling apoptosis induced by TNRI.