Associations between dental diseases and systemic outcomes are potentially important because of the high occurrence of dental diseases. If this extremely common source of chronic infection (dental disease) leads to an increased morbidity and mortality rate, the public health impact of oral disease on millions of Americans would be substantial. Recent studies demonstrate an association between dental and systemic diseases, including systemic infections, cardiovascular disease, pregnancy outcomes, respiratory diseases, and increased all-cause mortality rate. Because there are several common risk factors for oral and systemic diseases, and limitations in published studies, a careful interpretation is needed. Confounding (shared risk factors for both systemic and dental disease) may explain part of the reported associations. It is also plausible that there may be a causal link. It is likely that if there is a causal link, several pathways and mediators coexist, linking oral and systemic disease. Bacteremia, bacterial endotoxins, cytokines, and other inflammatory mediators could conceivably be playing a direct or indirect role. Missing teeth are a surrogate marker for previous dental infection, and may also lead to altered dietary intake. Hence, diet may be an additional mediator for several of these outcomes. We caution clinicians not to recommend extracting infected teeth, based on the periodontal-systemic disease associations, if the teeth do not warrant extraction otherwise, because loss of teeth and edentulousness are associated with increased risk of systemic diseases. When assessed against causal-defined criteria, the evidence suggests possible causal associations between chronic periodontal disease and tooth loss with cardiovascular disease, bacterial endocarditis, pregnancy outcomes, and all-cause overall mortality. Further studies are needed to show consistency, to corroborate that the associations are independent of common risk factors for both systemic and dental disease, including healthy lifestyle factors, and to evaluate different biological pathways.