The family of mammalian Nod-like receptors (NLRs) consists of critical intracellular immune proteins structurally related to plant resistance proteins. The NLRs NALP3 and IPAF, for example, can each form a multiprotein proinflammatory complex called the 'inflammasome', and mutations in the gene encoding Nod2, another NLR, are positively associated with Crohn disease. Here we show that many NLRs interacted with the ubiquitin ligase–associated protein SGT1 and heat-shock protein 90 (HSP90), both of which have plant orthologs essential for R-protein responses. 'Knockdown' of SGT1 by small interfering RNA or chemical inhibition of HSP90 abrogated inflammasome activity, and inhibition of HSP90 blocked Nod2-mediated activation of the transcription factor NF-κB and reduced NALP3-mediated gout-like inflammation in mice. Our data demonstrate a similarity in one type of innate immunity in plants and mammals that is consistent with convergent evolution of a shared mechanism.