In this study we investigated RIP1 kinase-dependent signaling pathways using mouse fibrosarcoma L929 cells that die by necroptosis when treated with the pan-caspase inhibitor zVAD.fmk. Altogether, our results suggest that Akt kinase is specifically engaged in signaling downstream from RIP1 kinase, which leads to a selective increase in its phosphorylation on Thr308, but not Ser473. According to our model (Fig. 9), necroptosis-associated phosphorylation of Akt requires two distinct signals. The first input, which is induced by growth factors, leads to the plasma membrane localization of Akt. Expression of a constitutively membrane-targeted Akt construct, Myr-Akt, overcomes the requirement for growth factors. At the same time, expression of Myr-Akt alone is not sufficient for the induction of necroptosis. A second, RIP1 kinase-dependent input is required for Thr308 phosphorylation of Akt in response to caspase inhibition and is essential for the propagation of the necroptotic signal.