Population studies have consistently shown that high-density lipoprotein (HDL) cholesterol levels are a strong, independent inverse predictor of cardiovascular disease. Every 1 mg/dl increase in HDL cholesterol is associated with a 2% to 3% decrease in coronary artery disease risk, independent of low-density lipoprotein (LDL) cholesterol and triglyceride levels. The primary mechanism for this protective effect is believed to be reverse cholesterol transport, but several other anti-inflammatory, anti-apoptotic, anti-oxidative functions for HDL have also been identified. Low HDL cholesterol is predictive of cardiovascular events in statin-treated patients with low LDL cholesterol, indicating that intensive lipid lowering strategies with statins alone are not sufficient to prevent cardiovascular events, and merging for additional effective HDL-raising therapy. This review focuses at giving an overview of current established HDL-raising pharmaca, including statins, fibrates, thiazolidinediones, and nicotinic acids, and of novel therapies including cholesterol ester transfer protein-inhibitors, liver X receptor agonists, reconstituted HDL, and apolipoprotein A-I mimetics. Working mechanisms are described and results from clinical trials of monotherapy and combination therapy are discussed.