The increasing prevalence of cardiovascular diseases cannot adequately be explained by traditional risk factors. Recently, accumulating evidence has suggested that gut microbiota‐derived numerous metabolites are contributors to atherosclerotic events. Among them, the role of trimethylamine N‐oxide (TMAO) in promoting atherosclerosis has gained attention. TMAO is reported to exert the proatherogenic effects by impacting on the traditional risk factors of atherosclerosis and is associated with high risk of cardiovascular events. Besides that, TMAO is involved in the complex pathological processes of atherosclerotic lesion formation, such as endothelial dysfunction, platelet activation and thrombus generation. In light of these promising findings, TMAO may serve as a potential target for atherosclerosis prevention and treatment, which is conceptually novel, when compared with existing traditional treatments. It is likely that regulating TMAO production and associated gut microbiota may become a promising strategy for the anti‐atherosclerosis therapy.