The inverse relationship between HDL and apolipoprotein A-I concentrations and the risk for premature atherosclerosis is well established, but the mechanism whereby apolipoprotein A-I offers protection is still somewhat elusive. Recent studies suggest that a specific subpopulation within the lipoprotein (AI) subclass may be more effective than others in promoting cholesterol efflux from cells. In addition, it appears that the lipid-free form of apolipoprotein A-I may have an important role in the antiatherosclerotic process. Unique new functions of apolipoprotein A-I-containing particles in modulating cytokines and lipid hydroperoxide transport, together with their role in antiatherogenesis, are also discussed. Current research with transgenic mice, however, indicates that apolipoprotein A-II must be taken into consideration in understanding the development of atherosclerosis, because it appears to be a potent antagonist for the protective properties of apolipoprotein A-I.