The innate immune system uses different molecules that sense pathogen associated molecular patterns. These include Toll-like receptors (TLRs), RIG-1-like receptors (RLRs) and the NOD-like receptors (NLRs). The NLRs, consisting of more than 20 related family members, are present in the cytosol and recognize intracellular ligands. Members of the NLR can be grouped into molecules that contain either a CARD or a Pyrin motif. The NOD proteins mediate NF-κB activation, whereas Pyrin molecules such as NALP3 regulate IL-1β and IL-18 production. In this review, we will discuss the role of NLRs in pattern recognition of microbial components and their role in health and disease.