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Plant defense responses against pathogens are triggered by perception of conserved microbe-associated molecular patterns (MAMPs). However, it remained unknown whether plants are able to detect conserved molecular patterns derived from nematodes, which likely represent the most abundant animals on earth. Here we show that plant parasitic nematodes produce small molecules called ascarosides (ascr), an evolutionarily conserved family of nematode pheromones, and that plants respond to these molecules by activating systemic defenses against a broad spectrum of pathogens. Low concentrations of ascr#18 (1nM-1µM), the most abundant ascaroside in plant parasitic nematodes, induce hallmark of defense responses in plants. Ascr#18 induced both salicylic acid- and jasmonic acid-mediated defense signaling pathways and enhanced resistance to virus, bacteria and nematode in Arabidopsis. Furthermore, we show that ascr#18 perception via roots or leaves increases resistance in tomato, potato, and barley to foliar bacterial, oomycete, or fungal pathogens. Our results indicate that monocots and dicots recognize ascarosides as a conserved molecular signature of nematodes that triggers conserved plant defense signaling pathways, similar to perception of MAMPs. Using potent small-molecule signals such as ascarosides to activate plant immune systems and protect plants against pathogens and pests has potential to improve the economic and environmental sustainability of agriculture.