Gamma-glutamyl transferase (GGT) is a ubiquitous cell surface enzyme that cleaves extracellular glutathione (G-SH) or other gamma-glutamyl compounds. GGT serves to increase the availability of amino acids, primarily cysteine, for intracellular G-SH synthesis and plays a crucial role in maintaining G-SH homeostasis and defense against oxidative stress in organisms. Measurement of circulating GGT activity is widely used for the diagnosis of liver and obstructive biliary diseases and as an indicator of alcohol consumption. Epidemiological studies suggest an association between elevated GGT activity level and a risk of incident coronary heart disease (CHD) or CHD-related mortality. Elevated GGT activity level is associated with a plethora of cardio-metabolic risk factors, including traditional cardiovascular risk factors, metabolic syndrome, systemic inflammation, oxidative stress burden and various comorbidities that incur a negative impact on patient risk profile and prognosis. Experimental studies and studies of human atherosclerotic plaques have revealed not only the presence of catalytically active GGT in atherosclerotic plaques, but also a correlation between GGT activity and indices of plaque instability, suggesting direct involvement in the pathophysiology of atherosclerosis and related clinical events via promotion of pro-oxidant reactions by the enzyme. However, it remains unknown whether GGT plays a direct role in the pathophysiology of atherosclerosis and CHD or is merely a correlate of coexisting cardiovascular risk factors. The exact molecular mechanisms of GGT participation in atherosclerosis or CHD and assessment of GGT-lowering therapies, as well as their impact on clinical outcomes, remain to be investigated in longitudinal studies.