Programmed cell death is a critical part of normal being in metazoan animals. Program cell death happens in two forms, apoptosis and necrosis. Apoptotic death is executed by a group of intracellular cysteine proteases, caspases, which are activated by apoptosis trigger. In contrast to apoptosis, the molecular mechanism of necrosis execution is poorly understood. Our laboratory has been using necrosis induced by TNF-a to study the biochemical pathway of necrosis. The programmed necrosis induced by TNF-a family of cytokines requires the activities of the receptor interacting serine-threonine kinases RIP1 and RIP3. Such form of cell death has now recognized to have important roles in animal development, tissue damage response, and innate immunity against microbes. In this seminar, I plan to discuss our recent progress in dissecting the molecular pathway downstream of RIP3 activation using a combination of tools from chemical biology, biochemistry and live cell imaging. We are able to map a necrotic pathway with discrete biochemical steps leading to the characteristic changes associated with necrosis. Moreover, we have identified a molecular marker in necrosis execution step that allows us to detect necrotic death in human diseased tissues.