Although lowering low-density lipoprotein (LDL) cholesterol with statins can substantially reduce cardiovascular morbidity and mortality, many treated patients retain a residual risk for cardiovascular events. Low levels of high-density lipoprotein (HDL) cholesterol may underpin this residual risk and may represent an additional target for intervention. Several new therapies for substantially increasing HDL cholesterol levels are under investigation, including cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I mimetics and recombinant HDL, liver X receptor (LXR) agonists, and peroxisome proliferator-activated receptor (PPAR) agonists. Combining new HDL cholesterol-elevating agents with existing LDL cholesterol-lowering agents may improve the cardiovascular risk reductions currently attainable.