Epidemiological and clinical intervention data have consistently shown that low levels of HDL-cholesterol (HDL-C) are associated with an increased risk of cardiovascular disease. In contrast, data for gene variants associated with changes in HDL-C are more conflicting, potentially reflecting the complexity of HDL metabolism. Indeed reverse cholesterol transport and HDL functionality cannot be appreciated by HDL-C level alone. In clinical practice, low HDL-C is frequently combined with other metabolic abnormalities, particularly with type 2 diabetes, metabolic syndrome and abdominal obesity. These circumstances are usually associated with the presence of an atherogenic dyslipidemia characterized by the lipid triad low HDL-C, elevated triglycerides and excess of small dense LDL particles. The first step in the management of low HDL-C is lifestyle interventions: weight loss, physical activity and smoking cessation are effective in increasing HDL-C. The residual cardiovascular risk among high risk patients who are treated with statins, have triggered intense interest in therapies raising HDL-C. Until now, nicotinic acid is the most effective drug. All the new therapeutic strategies acting on HDL should be validated by cardiovascular clinical trials.