High-density lipoprotein (HDL) therapy is an emerging area of therapeutic development in the cardiovascular field, aimed at supplementing and improving the vascular benefit exerted by current treatments. Several studies have clearly established that HDL-cholesterol (HDL-C) levels are a potent and independent epidemiologic risk factor for cardiovascular diseases; moreover, studies in animal models have established that HDL-C raising interventions, such as overexpression of apolipoprotein A-I (apoA-I), the major HDL protein component, reduce the extent of atherosclerosis. In vitro and in vivo experiments have provided mechanistic explanations for the atheroprotective effects of HDL. HDL not only mediates reverse cholesterol transport, but also exerts antioxidant, anti-inflammatory, antithrombotic and vasodilatory effects. These multiple antiatherosclerotic properties provide an excellent rationale for designing therapeutic interventions targeted at enhancing HDL/apoA-I levels, but also for considering a direct administration of HDL-apoA-I in a variety of cardiovascular diseases. We provide an overview and an update of all therapeutic applications of synthetic HDL tested in animal models or in clinical trials. HDL therapy has proven to be effective in promoting atherosclerosis regression not only in experimental models, but also in humans, whereas applications to other areas of cardiovascular disease have only, up to now, been tested in animal models.