Toll-like receptors (TLRs) and the nucleotide-binding domain, leucine rich repeat containing family (or Nod-like receptors, NLRs) are two important families of microbial sensors that are membrane-associated and cytosolic molecules, respectively. The Nod proteins Nod1 and Nod2 are two NLR family members that trigger immune defense in response to bacterial peptidoglycan. Nod proteins fight off bacterial infections by stimulating proinflammatory signaling and cytokine networks and by inducing antimicrobial effectors, such as nitric oxide and antimicrobial peptides. Nod1 is also critically implicated in shaping adaptive immune responses towards bacterial-derived constituents. In addition, recent evidence has demonstrated that mutations in Nod1 and Nod2 are associated with a number of human inflammatory disorders, including Crohn's disease, Blau syndrome, early-onset sarcoidosis, and atopic diseases. Together, Nod1 and Nod2 represent central players in the control of immune responses to bacterial infections and inflammation.