Patients with chronic kidney disease (CKD) have an enhanced risk of cardiovascular (CV) morbidity and mortality when compared with age- and gender-matched individuals with normal kidney function. Trimethlyamine N-oxide (TMAO) is a gut-derived amine oxide that has been implicated in the causation of CV diseases. Plasma TMAO is cleared by the kidney, and TMAO levels are elevated in CKD. Experimental studies have identified pathogenic mechanisms by which TMAO may contribute to CV disease through dysregulation of lipid metabolism, enhanced macrophage foam cell formation, and platelet dysfunction. Safe and well-tolerated therapeutic interventions such as pre- and probiotics, which modify the gut microbiome, offer the opportunity for interventional studies. This review examines the pathogenicity of TMAO, its value as a biomarker, and its potential as a therapeutic target in the context of CKD.