There is a distinct inverse relationship between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease risk. HDL-C mediates cholesterol efflux from the vasculature and promotes anti-oxidant, anti-inflammatory, and anti-thrombotic effects. There are multiple lifestyle and therapeutic interventions that raise HDL-C, and there is increasing evidence that these interventions improve cardiovascular outcomes. Recent findings regarding the role of HDL-C in cholesterol metabolism offer new strategies designed to target atherosclerosis. This review highlights the utility of existing HDL-C-raising strategies and examines new potential therapies.