The last 10 years have witnessed the identification of a new class of intracellular pattern-recognition molecules—the nucleotide-binding domain and leucine-rich repeat–containing family (NLR). Members of this family garnered interest as pattern-recognition receptors able to trigger inflammatory responses against pathogens. Many studies support a pathogen-recognition function for human NLR proteins and shed light on their role in the broader control of adaptive immunity and various disease states. Other evidence suggests that NLRs function in processes unrelated to pathogen detection. Here we discuss recent advances in our understanding of the biology of the human NLR proteins and their non-pathogen-recognition function in tissue homeostasis, apoptosis, graft-versus-host disease and early development.