Caspase-11 is activated by cytoplasmic lipopolysaccharide (LPS), leading to pyroptosis and endotoxic shock. This study shows that LPS, specifically penta- and hexa-acylated lipid A, triggers caspase-11 in mice, while tetra-acylated lipid A does not. Caspase-11 is involved in detecting cytosolic bacteria and is distinct from the canonical inflammasome pathway. Caspase-11 activation is independent of TLR4 and requires prior priming with LPS, poly(I:C), IFN-β, or IFN-γ. LPS in the cytosol activates caspase-11, leading to pyroptosis, IL-1β secretion, and shock. The study also shows that cytosolic pathogens like Francisella evade caspase-11 by modifying their lipid A structure. These findings suggest that caspase-11 is a key sensor for cytoplasmic LPS, contributing to endotoxic shock. The study highlights the importance of understanding caspase-11's role in immune responses and its implications in sepsis and Gram-negative septic shock.Caspase-11 is activated by cytoplasmic lipopolysaccharide (LPS), leading to pyroptosis and endotoxic shock. This study shows that LPS, specifically penta- and hexa-acylated lipid A, triggers caspase-11 in mice, while tetra-acylated lipid A does not. Caspase-11 is involved in detecting cytosolic bacteria and is distinct from the canonical inflammasome pathway. Caspase-11 activation is independent of TLR4 and requires prior priming with LPS, poly(I:C), IFN-β, or IFN-γ. LPS in the cytosol activates caspase-11, leading to pyroptosis, IL-1β secretion, and shock. The study also shows that cytosolic pathogens like Francisella evade caspase-11 by modifying their lipid A structure. These findings suggest that caspase-11 is a key sensor for cytoplasmic LPS, contributing to endotoxic shock. The study highlights the importance of understanding caspase-11's role in immune responses and its implications in sepsis and Gram-negative septic shock.