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Toll-like receptors and Nod-like receptors (NLR) play an important role in sensing invading microorgan-isms for pathogen clearance and eliciting adaptive immunity for protection against rechallenge. Nod1 and Nod2, members of the NLR family, are capable of detecting bacterial peptidoglycan motifs in the host cytosol for triggering proinflammatory cytokine production. In the current study, we sought to determine if Nod1/Nod2 are involved in sensing Bacillus anthracis infection and eliciting protective immune responses. Using mice deficient in both Nod1 and Nod2 proteins, we showed that Nod1/Nod2 are involved in detecting B. anthracis for production of tumor necrosis factor alpha, interleukin-1 (IL-1), IL-1, CCL5, IL-6, and KC. Proinflam-matory responses were higher when cells were exposed to viable spores than when they were exposed t