The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is a key rate-controlling step early in the cholesterol biosynthetic pathway that catalyzes the conversion of HMG CoA to mevalonic acid. Since this enzyme plays a significant role in regulating cholesterol synthesis, it is a rational target for pharmacologic intervention. The first potent, specific inhibitor of HMG CoA was mevastatin (compactin, ML-236B) which was discovered in 1976 by Endo et al. [J Antibiot 1976;29:1346-1348]. Subsequently, lovastatin, a novel, more active fungal metabolite was isolated from a strain of Aspergillus terreus.Lovastatin, the first of this class of agents to be approved for clinical use, was chemically modified to form simvastatin. Simvastatin is superior to lovastatin in intrinsic inhibitory potency. Both are inactive lactone prodrugs that must be converted to their respective dihy-droxy open-acid forms to elicit inhibitory activity. Pharmacologic characterization of lovastatin and simvastatin has demonstrated that these potent inhibitors of HMG CoA reductase specifically inhibit cholesterol synthesis in animal cells, as well as in vivo after oral administration of the agents. Oral administration of either lovastatin or simvastatin to dogs in the presence or absence of the bile acid sequestrant cholestyramine results in a marked, sustained lowering of plasma cholesterol. Associated with the cholesterol lowering is a decrease in urinary and plasma levels of mevalonic acid, the end product of the HMG CoA reductase reaction. The target organ for inhibitors of HMG CoA reductase is the liver, the primary site of cholesterol biosynthesis. Both lovastatin and simvastatin are preferentially extracted by this organ. In studies in the rat in which direct measurements of drug levels have been carried out, much more inhibitory activity derived from the prodrugs lovastatin and simvastatin is found in the liver than in spleen, testes, and kidney. This is reflected in a much greater in vivo inhibition of cholesterol synthesis in the liver by these agents than in the periphery. In summary, the HMG CoA reductase inhibitors lovastatin and simvastatin are potent inhibitors of mevalonic acid synthesis in vitro and in vivo. They are preferentially concentrated in the liver, the target organ. This results in inhibition of cholesterol synthesis and a concomitant decrease in plasma low-density lipoprotein cholesterol in experimental animals and humans.