Over the past few years the field of innate immunity has undergone a revolution with the discovery of pattern recognition molecules (PRM) and their role in microbe detection. Among these molecules, the Nod‐like receptors (NLRs) have emerged as key microbial sensors that participate in the global immune responses to pathogens and contribute to the resolution of infections. This growing group of proteins is divided into subfamilies with basis in their different signaling domains. Prominent among them are Nod1, Nod2, Nalp3, Ipaf, and Naip that have been shown to play important roles against intracellular bacteria. Furthermore, mutations in the genes that encode these proteins have been associated with complex inflammatory disorders including Crohn's disease, asthma, familial cold urticaria, Muckle‐Wells syndrome, and Blau syndrome. In this review we will present the current knowledge on the role of these proteins in immunity and inflammatory diseases.