Nod1 and Nod2 are no strangers to Hot Papers. Nor is Gabriel Nuñez, the University of Michigan pathologist whose back-to-back discoveries concerning the cytosolic proteins were featured last year. The 2001 papers by Nuñez and colleagues demonstrated Nod1 and Nod2 (also referred to as CARD15 and CARD4, respectively) sense intracellular pathogens and activate NF-κB, a transcription factor central to immunoregulation and inflammation, and that mutations in the Nod2 gene were a risk factor for Crohn disease.[1] At the time, there was some controversy as to what the Nod proteins sensed. Nuñez's assertion that the target was lipopolysaccharide (LPS), a bacterial cell-wall constituent, met with criticism from scientists who study LPS sensing.