The nucleotide-binding oligomerization domain-like receptor (NLR) family of proteins is involved in the regulation of innate immune responses and cell death pathways. Some NLR family members promote the activation of proinflammatory caspases within multiprotein complexes, called inflammasomes. Recent studies analyzing mice deficient in various components of the inflammasome have provided insight into the role of these molecules in host defense against pathogens and in autoinflammatory disorders. Here, we review these studies and propose that membrane disruption leads to activation of the inflammasome.