Host-microbes interaction plays a crucial role in cardiovascular disease (CVD) pathogenesis, mechanistically via metaorganismal pathways. The trimethylamine N-oxide (TMAO) metaorganismal pathway is the most deeply investigated one, which comprises trimethylamine precursors, such as choline, trimethylamine lyase, trimethylamine, host liver FMO3, TMAO, and downstream effectors involving unfolded protein response (UPR), NF-κB and NLRP3 inflammasome. Accumulating data from clinical investigations of CVD patient cohorts and rodent models have supported the critical role of this metaorganismal pathway in the pathogenesis of CVD. We summarize an array of significant animal studies especially for arthrosclerosis with an emphasis on downstream molecular effectors of this metaorganismal pathway. We highlight clinical investigations of the prognostic value of plasma TMAO levels in predicting prospective risk for future major adverse cardiac events (MACE) indicated by composite end points of myocardial infarction (MI), stroke, heart failure (HF), other ischemic cardiovascular events, or death. Further, we discuss the latest advances of preclinical models targeting the gut microbiota trimethylamine lyase of the TMAO metaorganismal pathway for CVD intervention, as well as the catalog of gut microbiota TMA lyase genes and microbes in the human gut as the prerequisite for potential clinical intervention. In-depth characterization of TMAO metaorganismal pathway holds great promise for CVD clinical metagenomics, diagnostics and therapeutics.