The ecological phenomenon of arthropods with defensive hairs is widespread. These urticating hairs can be divided into three categories: true setae, which are detachable hairs in Lepidoptera and in New World tarantula spiders; modified setae, which are stiff hairs in lepidopteran larvae; and spines, which are complex and secretion-filled structures in lepidopteran larvae. This review focuses on the true setae because their high density on a large number of common arthropod species has great implications for human and animal health. Morphology and function, interactions with human tissues, epidemiology, and medical impact, including inflammation and allergy in relation to true setae, are addressed. Because data from epidemiological and other clinical studies are ambiguous with regard to frequencies of setae-caused allergic reactions, other mechanisms for setae-mediated disease are suggested. Finally, we briefly discuss current evidence for the adaptive and ecological significance of true setae.