There is extensive evidence that necrosis plays a prominent role in a wide range of human pathological conditions, such as myocardial infarct, ischemic injury and neurodegeneration. Therefore, development of necrosis inhibitors is of high interest.A specific and potent small-molecule inhibitor of necroptosis, necrostatin-1 (Nec-1) has been identified by screening for chemical inhibitors of necrotic cell death in U937 cellsi nduced by TNF-a in the presence of caspase inhibitors. Nowadays, several structurally and functionally distinct necrostatins and corresponding modifications have been reported. The initial study showed that Nec-1 inhibits RIP kinase-induced necroptosis. This finding was confirmed later, when RIP1 kinase was identified as a specific cellular target of Nec-1, Nec-3 and Nec-5, but through distinct mechanisms. Nec-1 was shown to inhibit RIP1 kinase in a T-loop-dependent manner, binding preferentially to and stabilizing the inactive conformation of RIP1 kinase, thereby shifting the equilibrium toward the inactive state. In contrast to the mechanism of Nec-1 it was shown that Nec-5 inhibits RIP1 kinase indirectly. Those findings underline the critical role of active RIP1 kinase for necroptosis.