Oral diseases may affect general health and many systemic disorders have oral manifestations and implications for dental treatment. This article reviews examples of the oral manifestations of systemic diseases, including oral cancer, diabetes mellitus, and infection from HIV. In addition, the plausible link between periconceptional use of folic acid by the mother and the risk of facial clefts is reviewed. The possible associations between oral infections, specifically periodontal diseases, and both cardiovascular disease and the delivery of preterm low birthweight infants also are reviewed. These and other associations present challenges to dentists, who must evaluate the scientific evidence supporting the associations or alleged causality and select effective treatment options. Both of these challenges require in-depth knowledge of the scientific method, criteria to establish causality, and evaluation of the merit of possible treatment options; in turn, these requirements identify dentists as medical professionals who utilize prevention as the first option in health care, use oral tissues and saliva to diagnose systemic diseases, rely on medical facilities to order laboratory tests, and diagnose and treat patients in close collaboration with their medical colleagues.