Abstract: Nod1 and Nod2 are proteins involved in innate immune defense. These intracellular surveillance proteins detect bacterial peptidoglycan, although requiring distinct motifs to achieve sensing. Detection through Nod1 and Nod2 initiates proinflammatory signaling via NF-κB activation, which is necessary for clearance of infecting pathogens from the host. The peptidoglycan product sensed by Nod1 is a motif characteristic of Gram-negative bacteria plus some Gram-positive bacteria, such as Bacillus and Listeria spp. The specificity of Nod1 to detect this subset of bacteria might represent a selective advantage for the host in certain cases when Gram-negative bacteria represent the main threat, such as in the epithelial cells lining the intestinal mucosa. In contrast, Nod2 has been implicated as a general sensor for both Gram-positive and Gram-negative bacteria since muramyl dipeptide (MDP), which is the minimal motif in all peptidoglycans, is the structure recognized by Nod2. Mutations in Nod2 have been associated with autoinflammatory disease in humans, including Crohn's disease. Interestingly, the most common mutation in Nod2 associated with Crohn's disease results in protein product that no longer detects MDP. Although the implications of these findings are still not fully understood, it appears that lack of bacterial sensing through a loss of interaction between mutant Nod2 and MDP contributes to the pathology of disease. A loss of surveillance activity by Nod2 may result in the inability of local responses in the intestinal mucosa to control bacterial infection, thereby initiating systemic responses and leading to aberrant inflammation.