Atherosclerosis (AS), the pathological basis of most cardiovascular diseases, is a chronic inflammatory vascular disease with disorders of lipid metabolism. It is characterized by excessive lipid accumulation and foaming of macrophages and smooth muscle cells in the intima of blood vessels, which triggers atherosclerotic plaque development and subsequent thrombus formation. High-density lipoprotein (HDL) is a class of cholesterol-rich lipoprotein particles that transport cholesterol from peripheral cells to the liver for biliary excretion via reverse cholesterol transport (RCT), which is thought to be the basis of HDL’s anti-atherogenic properties. The inverse association between high-density lipoprotein-cholesterol (HDL-C) level and the risk of clinical events resulting from atherosclerosis is widely accepted. Therefore, targeting HDL therapeutically presents an attractive strategy for treating atherosclerotic cardiovascular disease. However, multiple epidemiological evidences have demonstrated that raising HDL-C does not certainly confer a clinical benefit. The cholesterol content of HDL may provide limited information on their antiatherogenic properties and the composition and particles’ structure provide more information on their functionality. HDL particles are, however, highly heterogeneous in structure and intravascular metabolism. Many critical proteins and enzymes have been discovered to regulate the levels, composition and structure of HDL. This paper mainly reviews the effects of various molecules on HDL metabolism and remodeling processes, as well as the research progress of related drugs targeting the above processes. Based on the relationship between HDL and RCT, we reviewed four aspects of AS therapeutic strategies for HDL modulation: (1) promoting cholesterol efflux from peripheral cells; (2) enhancing HDL esterification; (3) influencing HDL remodeling; (4) affecting hepatic uptake and intestinal excretion of HDL, which may provide a theoretical reference for a more comprehensive evaluation of the anti-atherogenic effects of HDL.