Intracellular lipopolysaccharide (LPS) from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11 causing pyroptotic cell death, IL-1 processing, and lethal septic shock. How caspase-11 drives these downstream signaling events is largely unknown. Here we show that Gasdermin-D (Gsdmd) is essential for caspase-11-dependent pyroptosis and IL-1 maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice linked Gsdmd to the intracellular LPS response. Macrophages from Gsdmd–/– mice generated by gene targeting also exhibited defective pyroptosis and IL-1 secretion induced by cytoplasmic LPS or Gram-negative bacteria. In addition, Gsdmd–/– mice were protected from a lethal dose of LPS. Mechanistically, caspase-11 cleaved Gsdmd and the N-terminal Gsdmd fragment promoted both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify Gsdmd as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacterial infection. At the meeting I’ll give an update on the discovery of an additional mediator of pyroptosis: IRF2, a transcriptional factor that drives the expression of Gsdmd. In it’s absence cells and mice are resistant to LPS challenge. In sum we have defined a new pathway for LPS responsiveness that may have therapeutic potential.