The putative intracellular microbial-sensor proteins Ipaf and Naip5 are required in macrophages to restrict intracellular growth of the bacterial pathogen Legionella pneumophila. We found that Ipaf and Naip5 appear to function in a pathway that senses the cytosolic presence of flagellin and triggers a rapid caspase-1-dependent death of the macrophage. Legionella mutants lacking flagellin failed to trigger caspase-1-mediated cell death and replicated freely in normally restrictive macrophages. The possible logic underlying flagellin-triggered cell death in the context of immunity will be discussed.