Current cholesterol treatment guidelines target low-density lipoprotein cholesterol as the primary goal of therapy and recommend statins as first line therapy. However, despite aggressive treatment and success at reaching the recommended goals, coronary heart disease is still a leading cause of morbidity and mortality. Thus, other lipoproteins, such as high-density lipoprotein, are now being looked to as the next promising targets of therapy to help reduce the burden of coronary heart disease and atherosclerosis. This review details currently available strategies to raise high-density lipoprotein cholesterol, and then turns to several new compounds in development that target the varying components of the complex metabolism of high-density lipoprotein.