The study identifies RIP1 kinase as the primary cellular target of necrostatins, a class of small-molecule inhibitors that prevent necroptosis, a form of programmed cell death. Necrostatin-1, a potent inhibitor of necroptosis, was found to inhibit RIP1 kinase activity *in vitro* and *in vivo*. Two other necrostatins, necrostatin-3 and necrostatin-5, also target RIP1 kinase but through distinct mechanisms. The results establish RIP1 kinase as a key upstream regulator of necroptosis and suggest that necrostatins could be developed as therapeutic agents for diseases involving necrotic tissue injury. Molecular modeling of the RIP1–necrostatin complex provides insights into the mechanism of inhibition.The study identifies RIP1 kinase as the primary cellular target of necrostatins, a class of small-molecule inhibitors that prevent necroptosis, a form of programmed cell death. Necrostatin-1, a potent inhibitor of necroptosis, was found to inhibit RIP1 kinase activity *in vitro* and *in vivo*. Two other necrostatins, necrostatin-3 and necrostatin-5, also target RIP1 kinase but through distinct mechanisms. The results establish RIP1 kinase as a key upstream regulator of necroptosis and suggest that necrostatins could be developed as therapeutic agents for diseases involving necrotic tissue injury. Molecular modeling of the RIP1–necrostatin complex provides insights into the mechanism of inhibition.