A chemical genetics study has identified a small-molecule inhibitor for a specialized programmed cell death process and revealed a previously unknown molecular component in the pathway that controls the process. Necroptosis—a form of necrosis, or cell death from extracellular causes such as infection and tissue damage—is controlled by a cellular signaling pathway. The pathway plays important roles in a variety of life processes, including development, response to tissue damage, and immune reactions to viruses. Xiaoguang Lei and Xiaodong Wang of China’s National Institute of Biological Sciences and coworkers used high-throughput chemical screening to identify necrosulfonamide as a compound that blocks necroptosis (Cell, DOI: 10.1016/j.cell.2011.11.031). Signaling molecules in the necroptosis pathway were previously known to include receptor-interacting serine-threonine kinases 1 and 3 (RIP1 and RIP3), but the target of necrosulfonamide turns out to be mixed-lineage kinase domainlike protein (MLKL). The study thus reveals MLKL to be a critical component of the necroptosis pathway, which was not known before. Necrosulfonamide “will be a very useful chemical probe for further biological studies,” Lei says.