In plants and animals, the NLR family of receptors perceives non-self and modified-self molecules inside host cells and mediates innate immune responses to microbial pathogens. Despite their similar biological functions and protein architecture, animal NLRs are normally activated by conserved microbe- or damage-associated molecular patterns, whereas plant NLRs typically detect strain-specific pathogen effectors. Plant NLRs recognize either the effector structure or effector-mediated modifications of host proteins. The latter indirect mechanism for the perception of non-self, as well as the within-species diversification of plant NLRs, maximize the capacity to recognize non-self through the use of a finite number of innate immunoreceptors. We discuss recent insights into NLR activation, signal initiation through the homotypic association of N-terminal domains and subcellular receptor dynamics in plants and compare those with NLR functions in animals.