After the discovery of gammaglutamyltranspeptidase in 1950 by Hanes, the significance of its increased levels in clinical practice has mainly been focused on ethanol toxicity, and also some neoplasms and biliary tract obstruction. More recently, attention has swift to the metabolic functions of this enzyme, as a neutralizer of oxygen free radicals and as a glutathione donor to the cell. High serum levels of gammaglutamyltranspeptidase is known to occur when oxidative stress is increased, or associated with several vascular risk factors and the insulin resistance syndrome, as an early marker of diabetes. There are also a number of drugs that induce the expression of the tissue enzyme (microsomes) with the result of high serum levels without structural damage to the liver. Because it is a ubiquitous enzyme, a very high number of causes can be involved, that may be difficult to recognize. Finally, because glutathione is necessary to conjugate a number of chemical compounds, from an epidemiological and toxicological perspective, the enzyme might be useful as a biomarker of several ambient toxins.In this review we want to emphasize the increasing clinical and diagnostic significance of this enzyme discovered half a century ago.