As a consequence of seminal laboratory and experimental work conducted in the 1970s, infections have recently been recognized among possible risk factors for atherosclerosis and its clinical cardiovascular disease manifestations. The infectious hypothesis also relates to modern atherogenesis theories that consider the crucial role of inflammation in the initial development as well as in the natural history of the atherosclerotic plaque. During the last 2 decades, numerous clinical and epidemiologic studies have explored the association between markers of chronic infections in relation to a variety of clinical and subclinical cardiovascular disease outcomes. These studies have focused on a variety of agents including herpesvirus (especially cytomegalovirus), Chlamydia pneumonia, Helicobacter pylori, and periodontal pathogens, and have produced inconsistent results. Some of the limitations and methodological issues in interpreting the existing epidemiologic evidence are discussed in this article. In addition, other supporting evidence is presented here, including pathology studies documenting the presence of infectious agents' DNA in atherosclerotic plaque tissue and experimental infection models in animal studies. Areas for future research are discussed in light of the strengths and limitations of the existing evidence.