Nod-like receptors (NLRs) are a family of intracellular sensors that play key roles in innate immunity and inflammation. While some NLRs, including Nod1, Nod2, NAIP and IPAF, detect conserved bacterial molecular signatures from within the host cytosol, other members of this family seem to have evolved the capacity to sense danger signals perhaps independently of a microbial trigger. This is illustrated by the discovery that Nalp3 and Nalp1 are specifically activated by low concentrations of intracellular potassium. The fact that several stimuli, including bacterial toxins and some viruses, but also sterile crystals made of uric acid, asbestos or aluminium hydroxide, can trigger the Nalp3 inflammasome illustrate the fascinating prospect that microbial infections and certain danger signals may be perceived similarly by host recognition systems. Gaining insight into the function of NLR proteins in general will impact considerably on our understanding of the mechanisms underlying immunity to infection, adjuvanticity and auto-inflammatory disorders. In this review, we summarize the current knowledge on the microbial- and danger-derived signals that activate NLRs.