The Nod-like receptor family in man contains proteins that recognize invasive bacteria. Nod1, a member of this family, is activated by specific peptidoglycan-derived muropeptides that contain meso-diaminopimelic acid. Plants contain a large family of proteins known as resistance (R) proteins that have common structural features with the Nod-like receptors and are essential for protection against a variety of plant pathogens. Extensive genetic studies have shown that the R protein function is determined by multiple proteins including SGT1, Rar1, and HSP90. Here we show that SGT1 positively regulates Nod1 activation. Depletion of SGT1 with siRNA did not affect stability of Nod1 protein or of downstream signaling molecules but did prevent multiple cellular responses associated with Nod1 activation. In contrast, depletion of the mammalian orthologue of Rar1, Chp1, had no effect on Nod1-dependent cellular activation. Finally, depletion of HSP90 or addition of a pharmacologic inhibitor of HSP90 resulted in loss of Nod1 protein. Thus, we show common regulatory pathways in plant R protein and human Nod1-dependent pathways and provide the basis for understanding the Nod1 pathway.