This chapter focuses on the strategies and agents that improve the function of high density lipoprotein (HDL), specifically, ApoA-I mimetic peptides. A reduction in HDL is associated with increased severity of coronary artery disease (CAD) and an independent risk factor for cardiovascular disease (CVD). An increase in HDL also reduces vascular complications associated with sepsis, diabetes, and atherosclerosis, conditions that occur with greater frequency in aging populations. The approaches for raising HDL include both nonpharmacological and pharmacological strategies. Exercise, weight loss, alcohol consumption, and cessation of tobacco use are nonpharmacological modifications that are associated with a 5-10% increase in HDL-C. Pharmacological agents that increase HDL levels comprise a number of different drug classes. Peptide mimetics of apolipoproteins A-I, E, and J exert antiinflammatory and atheroprotective effects in dyslipidemic animal models. Peptide mimetics increase circulating levels of lipid-poor preb-HDL particles that are effective mediators of cholesterol efflux from macrophages. They also increase the activity of the HDL-associated enzyme PON-1, which reduces low density lipoprotein (LDL) atherogenicity by hydrolyzing oxidized lipids. Vasoprotective effects of apolipoprotein mimetics also include an increase in the expression of the antioxidants HO-1 and EC-SOD. These enzymes decrease oxidant stress and the formation of proinflammatory lipid peroxides. The ApoA-I mimetic 4F is currently undergoing clinical evaluation and has been shown to be safe and well tolerated in phase I studies. These results underscore the therapeutic potential of apolipoprotein mimetic peptides in the treatment of cardiovascular diseases. © 2010 Elsevier Inc. All rights reserved.