Residual cardiovascular risk despite lowering LDL-cholesterol has stimulated research to develop strategies that promote the protective properties of HDL-cholesterol. Population and animal studies have suggested that HDL plays an important role in protection against cardiovascular disease. As a result, considerable interest has focused on the development of new therapies that substantially raise levels of HDL-cholesterol. The highly publicized failure of the cholesteryl ester transfer protein inhibitor torcetrapib has fuelled speculation that raising HDL-cholesterol may not be a viable strategy for the development of new therapies. It has also highlighted the complexity of the relationship between HDL and protection from cardiovascular disease. Accordingly, functionality has become an important factor for consideration in the development of new agents that raise HDL-cholesterol. The evidence for the biological activity of HDL, and both existing and emerging therapeutic strategies are reviewed.