Although attractive, the microbial pathogenesis theory for atherosclerosis remains unproven. Over the last century, microbiologists have invoked fulfillment of Koch's postulates to determine pathogen causality. Certainly a multifactorial disease process such as atherosclerosis unlikely will be due to a single microbial agent, an agent when transferred to another host, will always induce atherosclerosis. Conflicting epidemiological data also do not support a single causative agent. However, as presented here, considerable in vitro, animal, and human epidemiological data support the plausibility that infectious agents can promote a proinflammatory, procoagulant and proatherogenic environment in the vessel wall. Microbial genes and molecules can catalyze these processes and foil normal cellular events. But, must intact microbes enter the vessel wall or can microbial molecules incite immune responses from afar? A new focus on pathogen-induced auto-immunity toward vasculature has been presented. For example, microbes contain molecules that mimic host cellular components (55). An immune response to a pathogen may cross react with vessel wall cellular structures. This immune response enhanced by infection may lead to high levels of cross reacting auto-antibodies or auto-aggressive T-cells. Epstein has championed the concept of pathogen burden in support of this auto-immune theory (56). Individuals infected with multiple pathogens such as HSV-1, HSV-2, CMV, Helicobacter pylori, and Hepatitis A, have high C-reative protein levels (markers of inflammation) and the greatest relative risk for coronary artery disease (57). Thus, pathogens might contribute to the atherosclerotic process by promoting inflammatory responses. It is this author's view that microbes and inflammation do play a role in the pathogenesis of atherosclerosis (58). Infection may contribute to the process promoting vessel wall injury initiated by oxidized lipids, smoking derived oxidants, hypertensive shear or diabetes glyoxidized molecules. Inflammation and immune reactions in response to infection can exacerbate and act synergistically with all of the aforementioned vasculotoxic moieties. Continued investigations in the 21st century will determine if vaccines, antibiotics, anti-inflammatory agents or immunosuppressants will alter the picture the early 19th century pathologists observed under their monocular microscopes.