Inhibition of ACAT, the enzyme which catalyses the intracellular formation of cholesteryl esters, is a very attractive target for the treatment of hypercholesterolaemia and atherosclerosis. However, in the past years many ACAT inhibitors gave disappointing results in clinical trials showing very low efficacy. In addition, their development was affected by the adrenotoxicity observed in many compounds. The discovery of two isoforms of the enzyme, namely ACAT1 and ACAT2, with different substrate specificity and different potential function, offers a precious information for planning selective inhibitors with reduced secondary effects. Today some potent, bioavailable and non adrenotoxic ACAT inhibitors are under clinical evaluation. Amongst others, a very promising compound is Avasimibe, presently in phase III clinical trials as anti-hyperlipidemic and anti-atherosclerotic agent. Finally, ACAT inhibitors have recently been proposed for the treatment of Alzheimers disease.