Metabolic disorders are associated with an increased risk of cardiovascular disease (CVD), and are commonly characterized by a low plasma level of high-density lipoprotein cholesterol (HDL-C). Although cholesterol lowering medications reduce CVD risk in these patients, they often remain at increased risk of CVD. Therapeutic strategies that raise HDL-C levels and improve HDL function are a potential treatment option for reducing residual CVD risk in these individuals. Over the past decade, understanding of the metabolism and cardioprotective functions of HDLs has improved, with preclinical and clinical studies both indicating that the ability of HDLs to mediate reverse cholesterol transport, inhibit inflammation and reduce oxidation is impaired in metabolic disorders. These cardioprotective effects of HDLs are supported by the outcomes of epidemiological, cell and animal studies, but have not been confirmed in several recent clinical outcome trials of HDL-raising agents. Recent studies suggest that HDL function may be clinically more important than plasma levels of HDL-C. However, at least some of the cardioprotective functions of HDLs are lost in acute coronary syndrome and stable coronary artery disease patients. HDL dysfunction is also associated with metabolic abnormalities. This review is concerned with the impact of metabolic abnormalities, including dyslipidemia, obesity and Type 2 diabetes, on the metabolism and cardioprotective functions of HDLs.