Low levels of HDL cholesterol are a significant predictor of atherosclerotic cardiovascular events. HDL is believed to protect against atherosclerosis by promoting reverse cholesterol transport, and potentially through anti-inflammatory, antioxidative, antithrombotic and nitric oxide effects. The multiple mechanisms of action, as well as a limited ability to measure these properties, make HDL a complex therapeutic target, albeit one with immense potential for the treatment of patients with atherosclerosis. Here, we discuss new therapeutic strategies currently being developed, which have the potential to increase plasma levels of HDL cholesterol and/or improve HDL function.