Inflammasomes are sensors that serve as activation platforms for caspase-1-a mechanism that set the prevailing paradigm for int ammatory caspase activation.A recent Nature paper by Shiet al.upends this paradigm by describing an unprecedented model for caspase activation whereby caspase-4,-5,and-11 directly bind their agonist,cytosolic LPS,triggering auto-activation and subsequent pyroptotic cell death.