The incidence of cardiovascular disease (CVD) increases with age and is associated with some syndromes that exhibit aspects of premature aging, such as progeria. Various factors are thought to contribute to the progression of CVD, including hypertension, hypercholesterolemia, diets rich in saturated and trans fats, etc. Recent reports have uncovered an important connection between diet, the microbiome, and CVD. Dietary carnitine (present predominately in red meat) and lecithin (phosphatidyl choline) are shown to be metabolized by gut microbes to trimethylamine (TMA), which in turn is metabolized by liver flavin monoxygenases (especially FMO3 and FMO1) to form trimethylamine-N-oxide (TMAO). High levels of TMAO in the blood strongly correlate with CVD and associated acute clinical events. Plasma TMAO levels may be an important clinical biomarker for CVD. The data suggest that that presence of specific as yet unidentified microorganisms in the gut linked to diet are required for high TMAO levels and TMAO-mediated CVD progression. Development of novel therapeutic approaches to manipulate gut flora may help treat CVD.