Clinical and molecular research on inflammation has soared tremendously thanks to the discovery of Toll-like receptors (TLRs). These efforts have resulted in the recent identification and characterization of a new class of proteins called NOD-like receptors (NLR), which are intracellular analogs of the TLRs. These molecules act as true sensors of the dangers encountered by the cell and are essential for the initiation of the inflammatory response. Their implication in the pathogeny of numerous auto-inflammatory and autoimmune diseases revolutionizes our understanding of the mechanisms underlying the development of these diseases. We discuss here these major discoveries as well as their clinical implications.