Background: Inflammation plays a major role in the development and progression of cardiovascular disease (CVD) morbidity and mortality. The well-established relationship between periodontal disease (PD) and CVD may be causal. Left untreated, PD can lead to high systemic inflammation, thus contributing to inflammatory CVD, such as atherosclerosis. Multiple mechanisms have been proposed to elucidate the causal relationship between PD and its contribution to CVD. Objective: This review article highlights the current evidence supporting the role of PD in the development and progression of atherosclerosis. Methods: After creating a list of relevant medical subject heading (MeSH) terms, a systematic search within PubMed in English for each MeSH term between 2000 and 2019 was used to generate evidence for this review article. Conclusion: There is overwhelming evidence in the current literature that supports an association between PD and CVD that is independent of known CVD risk factors. However, the supporting evidence that PD directly causes CVD in humans continues to remain elusive. Multiple biologically plausible mechanisms have been proposed and investigated, yet most studies are limited to mouse models and in vitro cell cultures. Additional studies testing the various proposed mechanisms in longitudinal human studies are required to provide deeper insight into the mechanistic link between these 2 related diseases.