High-density lipoprotein cholesterol (HDL-C) is a strong and independent predictor of major cardiovascular events in a wide range of patients. The relationship between HDL-C cholesterol and cardiovascular risk appears to be linear, continuous, negative and independent of other risk factors such as blood pressure, smoking and BMI. In addition, the inverse relationship between HDL-C and cardiovascular events does not depend on low-density lipoprotein cholesterol (LDL-C) levels, so a substantial residual cardiovascular risk is maintained also in individuals with LDL-C levels below the target recommended by scientific guidelines. Furthermore, a strong relationship among HDL-C levels, progression of atherosclerosis and risk of cardiovascular diseases has been also demonstrated. Treatments that increase HDL-C levels have been shown to be effective in reducing incidence of cardiovascular diseases both in primary and secondary prevention settings. However, proof that increasing HDL-C levels by pharmacological treatment is able to confer a reduction in major cardiovascular outcomes independent of changes in LDL-C or triglycerides levels is not completely defined. Among currently available compounds, statins do not seems to have a sufficient effect on HDL-C profile. Studies on fibrates have shown inconclusive results. Although niacin has been demonstrated to reduce the incidence of major cardiovascular events paralleling the regression of atherosclerosis, significant side-effects still limit its use. The potential benefit of cholesterol ester transfer protein inhibition is still under investigation. The combination therapy of fibrates with statins is also controversial. Thus, despite the potentially favorable effect of raising HDL-C levels, the available guidelines still do not consider HDL-C levels as a specific target for therapy. Further studies are needed to assess the role of new compounds to raise HDL-C levels or modify HDL composition and functionality.