Much work has been published on the association between periodontal disease and systemic disease, including original reports, narrative reviews, systematic reviews, and meta-analyses. Based on the existent work, one can assign an evidence level and grade, using standard evidence-based criteria, to the data available in the four major categories of medical outcomes studied: cardiovascular/cerebrovascular, pregnancy, pulmonary, and diabetes. We discuss methodologic and conceptual problems in the study of oral-systemic associations, focusing as an example on the association between periodontal disease and cardiovascular/cerebrovascular disease. We argue that the hierarchical ranking of studies by levels of evidence may be misleading. In particular, while randomized controlled trials (RCTs) are needed to determine the efficacy of periodontal treatment to reduce the risk of cardiovascular events, they may be of limited value in determining the etiologic role of periodontal disease on coronary heart disease and stroke. We discuss limitations of RCTs as well as the limitations of currently available data from epidemiologic studies, including study design and confounding and misclassification errors. We conclude that well-designed observational studies into the associations between periodontal disease and systemic disease need to remain an integral component of future research efforts in order to fully understand such associations.