High-density lipoprotein (HDL) is well known strongly to protect against atherosclerosis. Low HDL has not been an important target of medical treatment, however, largely due to a lack of convincing clinical trial data showing benefits of HDL raising therapy. Two recent breakthroughs in HDL research are now changing our clinical perspective on treatment of HDL deficiency. First, basic studies have enhanced our understanding of HDL metabolism and its anti-atherosclerotic mechanisms. Evidence is increasing for HDL’s role in reverse cholesterol transport, and for its antioxidant, pro-endothelial and anti-thrombotic effects. Second, clinical trials have better established benefits of treatment of HDL deficient patients, where statin and fibrate treatment have significantly reduced clinical cardiovascular events. Also, two pharmacologic agents useful for HDL raising have newly become available in the US, facilitating treatment of HDL deficiency. As a result, thresholds and goals for HDL raising are being increased from 35 to 40 mg/dL or higher.Treatment of low HDL begins with smoking cessation, regular physical activity, and weight reduction, as indicated. Drug therapy may then be indicated for HDL levels remaining below goal in cases of secondary prevention or high-risk primary prevention. Niacin is the most effective agent for HDL raising, and the new intermediate release Niaspan is easier to use than the traditional immediate-release form. Fibrates and statins may be first-line agents for HDL deficiency in cases with concurrent hypertriglyceridemia or hypercholesterolemia, respectively. Oral estrogen replacement raises HDL in postmenopausal women, but its use is controversial.Lifestyle and pharmacologic regimens for HDL raising are of increasing clinical importance for atheroprevention in high-risk patients with HDL deficiency.