There is increasing appreciation that changes in microbiome composition and function can promote long-term susceptibility for cardiometabolic risk. Gut microbe-derived metabolites that are biologically active, such as trimethylamine N-oxide (TMAO), are now recognized as contributors to atherogenesis. This review summarizes our current understanding of the role of TMAO in the pathogenesis of cardiometabolic diseases and will discuss current findings, controversies, and further perspectives in this new area of investigation. Better appreciation of the interactions between dietary nutrient intake with gut microbiota-mediated metabolism may provide clinical insights into defining individuals at risk for disease progression in cardiometabolic diseases, as well as additional potential therapeutic targets for reducing risks for cardiometabolic disease progression.