Although separated by more than one billion years of evolution, plants and animals have hit upon similar immune strategies to protect themselves against pathogens. One important mechanism is defined by cytoplasmic receptors called NLRs that, in plants, recognize so-called effectors, molecules that invading microorganisms secrete into the plant’s cells. These recognition events can either involve direct recognition of effectors by NLRs or indirect recognition, in which the NLRs act as ‘guards’ that monitor additional host proteins or ‘guardees’ that are modified by effectors. Host recognition of effectors, whether direct or indirect, results in cell death to confine microbes to the site of infection. However, until now, a detailed understanding of the mechanisms of action of plant NLRs has been lacking, and much of our understanding of how these molecules function in plants has been based on comparison with animal counterparts.