Plasma levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the incidence of atherosclerotic cardiovascular disease. The cardioprotective effects of HDL have been attributed to its role in reverse cholesterol transport (RCT) and especially the macrophage-dependent RCT, and also to the antioxidant properties of HDL as well as its direct effects on endothelial function. However, few of these effects have been verified in vivo in humans. With the creation and detailed analysis of genetically-engineered mice, a solid body of new information has emerged on the mechanisms controlling these key antiatherogenic functions of HDL and their effects on atherogenesis. This article provides a review of new insights into the molecular mechanisms underlying these three most studied antiatherogenic functions of HDL in vivo with a focus on genetically-engineered mice.