The last common ancestor of plants and animals may have lived 1 billion years ago. Plants and animals have occasionally exchanged genes but, for the most part, have countered selective pressures independently. Microbes (bacteria, eukaryotes, and viruses) were omnipresent threats, influencing the direction of multicellular evolution. Receptors that detect molecular signatures of infectious organisms mediate awareness of nonself and are integral to host defense in plants and animals alike. The discoveries leading to elucidation of these receptors and their ligands followed a similar logical and methodological pathway in both plant and animal research.