The study investigates the activation of caspase-11, an inflammatory caspase, in response to cytoplasmic lipopolysaccharide (LPS) in mice. Caspase-11 is known to induce pyroptosis, a form of programmed cell death, and is crucial for defense against bacterial pathogens that invade the cytosol. However, excessive activation of caspase-11 during endotoxemia can lead to shock. The researchers found that contamination of the cytoplasm by LPS triggers caspase-11 activation, specifically responding to penta- and hexa-acylated lipid A, while tetra-acylated lipid A is not detected. This suggests a mechanism of evasion for cytosol-invasive *Francisella*. Priming the caspase-11 pathway *in vivo* made both wild-type and *Tlr4*-deficient mice highly sensitive to subsequent LPS challenge, whereas *Casp11*-deficient mice were relatively resistant. These findings reveal a new pathway for detecting cytoplasmic LPS and highlight the importance of understanding the distinct signaling pathways involved in Gram-negative and Gram-positive sepsis.The study investigates the activation of caspase-11, an inflammatory caspase, in response to cytoplasmic lipopolysaccharide (LPS) in mice. Caspase-11 is known to induce pyroptosis, a form of programmed cell death, and is crucial for defense against bacterial pathogens that invade the cytosol. However, excessive activation of caspase-11 during endotoxemia can lead to shock. The researchers found that contamination of the cytoplasm by LPS triggers caspase-11 activation, specifically responding to penta- and hexa-acylated lipid A, while tetra-acylated lipid A is not detected. This suggests a mechanism of evasion for cytosol-invasive *Francisella*. Priming the caspase-11 pathway *in vivo* made both wild-type and *Tlr4*-deficient mice highly sensitive to subsequent LPS challenge, whereas *Casp11*-deficient mice were relatively resistant. These findings reveal a new pathway for detecting cytoplasmic LPS and highlight the importance of understanding the distinct signaling pathways involved in Gram-negative and Gram-positive sepsis.