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This review summarizes currently available therapies for raising high-density lipoprotein cholesterol (HDL-C) and expands on therapies currently in development that target high-density lipoprotein cholesterol.In the realm of new high-density lipoprotein-raising therapies, there is a strong focus on high-density lipoprotein metabolism and the reverse cholesterol transport pathway. Several infusions of recombinant apoA-I Milano/phospholipid complexes appeared to reduce atheroma volume as measured by intravascular ultrasound. Both intravenous and oral apoA-I mimetic peptides are in early clinical trials. Next generation PPAR-α agonists are more potent at high-density lipoprotein-raising than currently available fibrates, and dual PPAR-α/PPAR-γ agonists are under investigation to help correct atherogenic dyslipidemia seen in many diabetics. Two small molecule inhibitors of the cholesteryl ester transfer protein have shown promise in clinical trials at substantially raising high-density lipoprotein cholesterol.Larger scale clinical trials, including those with additional surrogate outcome measures as well as cardiovascular event outcomes are needed to further assess the benefit of newer high-density lipoprotein-raising therapies. Additional therapeutics are currently in development that target other parts of the reverse cholesterol transport pathway and, in addition to providing new potential pharmaceuticals, will help to further elucidate the atheroprotective mechanisms of high-density lipoprotein cholesterol.