The association between cardiovascular events and a high low-density lipoprotein (LDL) cholesterol level has been clearly established by numerous clinical trials. Moreover, reducing the LDL-cholesterol level using statins has been shown to be highly effective in both primary and secondary prevention. Nevertheless, despite statin treatment, the residual cardiovascular risk remains high and a large number of cardiovascular events still occur. On the other hand, a growing number of studies have demonstrated that there is an inverse association between the high-density lipoprotein (HDL) cholesterol level and cardiovascular risk. The most recent observations indicate that increasing the HDL-cholesterol level confers an additional benefit to reducing the LDL-cholesterol level with statins. Together, these findings justify turning our attention to HDL-cholesterol to provide a novel additional strategy for reducing cardiovascular risk. This review article describes: firstly, epidemiological studies that endorse HDL cholesterol as a therapeutic target; secondly, the different alternative treatments available for increasing the HDL-cholesterol level; and, finally, the benefits associated with such an increase.