Evidence now confirms that noncommunicable chronic diseases can stem from infectious agents. Furthermore, at least 13 of 39 recently described infectious agents induce chronic syndromes. Identifying the relationships can affect health across populations, creating opportunities to reduce the impact of chronic disease by preventing or treating infection. As the concept is progressively accepted, advances in laboratory technology and epidemiology facilitate the detection of noncultivable, novel, and even recognized microbial origins. A spectrum of diverse pathogens and chronic syndromes emerges, with a range of pathways from exposure to chronic illness or disability. Complex systems of changing human behavioral traits superimposed on human, microbial, and environmental factors often determine risk for exposure and chronic outcome. Yet the strength of causal evidence varies widely, and detecting a microbe does not prove causality. Nevertheless, infectious agents likely determine more cancers, immune-mediated syndromes, neurodevelopmental disorders, and other chronic conditions than currently appreciated.