Accumulation of cholesteryl ester (CE) stored as cytoplasmic lipid droplets is the main characteristic of macrophage foam cells. It is central to the development of atherosclerotic plaques. Since only unesterified or free cholesterol (FC) can be effluxed from the cells to extracellular cholesterol acceptors, hydrolysis of CE is the obligatory first step in CE mobilization from macrophages. This reaction, catalyzed by neutral cholesteryl ester hydrolase (CEH), is increasingly being recognized as the rate-limiting step in FC efflux. CEH, therefore, regulates the process of reverse cholesterol transport and ultimate elimination of cholesterol from the body. In this review, we discussed the characteristics of the various candidates recognized to date and examined their roles in hydrolyzing cellular CE and thus regulating atherogenesis. We aim to provide clues for using hydrolase as a therapeutic target for atherosclerosis.