Low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with an increased risk of coronary heart disease in prospective population studies and clinical trials of high-risk patients treated with a low to moderate intensity statin. As a result, therapeutic targets were developed to increase concentrations of HDL-C. Subsequently, clinical trials of high-intensity statins have not supported this previously well-established association. In trials of high-intensity statin therapy, low HDL particle concentration (HDL-P) has been associated with an increased risk of future cardiovascular events. Therefore, strategies that increase HDL-C without expanding the pool of HDL-P with its rich proteome/lipidome do not seem to be an effective strategy. In this review, we discuss potential mechanisms of action for the anti-atherogenic effect of HDL and the impact of current and emerging therapies on the functional capacity of HDL-P. Finally, we discuss emerging therapies that increase the concentration and functional properties of HDL.