The beneficial effects of high-density lipoprotein (HDL) on atherosclerosis have largely been attributed to its major protein, apolipoprotein A-I (apoA-I). Used as a therapeutic intervention, apoA-I is a large protein that requires venous administration, and is both difficult and expensive to manufacture. Because of these problems with apoA-I, the generation of smaller, easier to manufacture apoA-I mimetic peptides has become a target for pharmacologic development in the therapeutic management of human atherosclerosis. A potent apoA-I mimetic peptide, 4F, was found to have significant activity in various inflammatory states in both mice and monkeys. The anti-inflammatory and antiatherogenic effects of 4F include increased pre-beta HDL formation, increased cholesterol efflux, the conversion of pro-inflammatory HDL to anti-inflammatory HDL, and reduced lipoprotein oxidation. In addition, improved arterial vasoreactivity is another important function of 4F. In a rat model of diabetes, D-4F increased arterial concentrations of heme oxygenase-1 (HO-1) and superoxide dismutase, decreased superoxide levels, reduced levels of circulating endothelial cells, decreased endothelial cell fragmentation, and restored arterial vasoreactivity to normal. In a mouse model of systemic sclerosis, D-4F functioned to improve vasodilation and angiogenic potential, while reducing myocardial inflammation and oxidative stress. With respect to mouse models of heart transplant-associated atherosclerosis, D-4F induced HO-1. In addition, D-4F was shown to improve cognitive performance in low-density lipoprotein-receptor null mice with Western diet-induced cognitive decline. D-4F also reduced the kidney content of oxidized phospholipids in a mouse model of hyperlipidemia-induced renal inflammation. In early human studies in patients with significant cardiovascular risk, a single dose of oral D-4F was found to safely improve the anti-inflammatory index of HDL. L-4F is also being studied in clinical trials as a potential treatment modality for obesity and the metabolic syndrome.