In humans, 23 NLRs have been identified. These have been hypothesized to have distinct biological functions based on sequence and structure modeling analysis. To date, however, only a few NLRs have been studied intensively and the activating stimuli, physiologic functions, and relevant signaling pathways of most members of the NLR family are unknown or poorly defined. Genetic mutations and polymorphisms in NLRs are associated with a host of severe human autoinflammatory and autoimmune disorders, ranging from rare hereditary periodic fever syndromes (NLRP3) and early-onset sarcoidosis (NOD2) to more common disorders such as rheumatoid arthritis (CIITA), vitiligo (NLRP1), inflammatory bowel diseases (NOD1 and NOD2) and gastric cancer (NOD1), to name a few. We are undertaking systems-level approaches to understand NLR signaling pathways, their regulation, and the diseases resulting from NLR dysfunction. Our recent work has shown that a small sustained increase in NOD1 expression triggers ligand-independent inflammatory and oncogene responses providing insight into how a quantitatively small change in protein abundance can produce marked changes in cell state that can serve as the initiator of disease.