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Coronary artery disease (CAD) has a high prevalence and one of the principal drivers of mortality worldwide. Therefore, there is a requirement to develop sensitive diagnostic biomarkers, disease progression control and therapeutic stratification in order to keep a check on the disease rate. Atherosclerosis is a systemic disease, the main cause of heart disease, is associated with hyperlipidemia and lipid oxidation and has always been a common single leading cause of death in well-developed countries. In the attempts to study CAD and the causative agents for the disease, a metabolite circulating in the plasma termed trimethylamine-N-oxide (TMAO) has been found out to be an independent risk factor that increases CAD risk. The use of a metabolomic approachhas proven useful in the recent past, as it can aid in the identification and quantification of several metabolites that play a crucial role for diagnosis and exploring therapeutic targets. TMAO is majorly synthesized by a process which involves the bioconversion of gut microbiota and hepatic flavin monooxygenases (FMOs) from nutrient-containing dietary trimethylamine (TMA). TMA is synthesizedby gut bacterial fermentation from the components present in meat such as phosphatidylcholine (PC), betaine, choline, and L-carnitine. It can accentuate the process of atherosclerosis through the novel meta-organismal metabolic pathway. TMAO leads to atherogenesis by increasing vascular inflammation, reducing vascular functions and disrupting cholesterol homeostasis at various levels. This review article attempts to summarize the pool of evidence collectedon the microbiota-dependent TMAO and its association with atherosclerosis. We performed literature search with Medline, PubMed, and Google Scholar, on "TMAO in CAD", "metabolites in CAD" and "TMAO in other diseases" from the year 1990 to 2020. Although the circulatory TMAO has been identified as an independent marker for CAD, there is still no conclusive evidence to justify its role as a routine marker for CAD diagnosis. Future research must clarify the mechanisms which underpin these complex associations to determine if there is a causal link exists between TMAO and CAD. [ABSTRACT FROM AUTHOR]