For decades, the focus of therapy to mitigate cardiovascular risk has been to lower low density lipoprotein cholesterol (LDL-C), so called “bad cholesterol”. Widespread use of statins has resulted in a large body of clinical experience, which indicates that lower LDL-C levels do indeed correlate with decreased risk of cardiovascular and coronary artery diseases (CVD and CAD). Given these findings, recommended targets for LDL-C levels are continually being revised lower. Interestingly, however, even at low LDL-C levels there remains a substantial residual risk of CVD and CAD, particularly in patients with additional contributing factors. Recent post-hoc analyses of several large lipid modulation trials specifically assessing high density lipoprotein cholesterol (HDL-C) have revealed that increased HDL-C levels confer additional benefit against risk of CVD and CAD, even when LDL-C levels are already low. Human clinical outcomes trials that specifically target increasing HDL-C have not yet been conducted. However, the strong epidemiological inverse correlation between HDL-C and CVD risk remains. Discovery efforts aimed at increasing circulating levels of HDL-C have increased dramatically in recent years. This review will cover recent efforts and agents being developed such as cholesterol ester transfer protein inhibitors and nicotinic acid receptor agonists among other potential strategies.