Abstract: Atherosclerosis (AS) is the key reason for myocardial infarction and stroke, which is estimated to be the first health killer in 2020. Strategies to prevent AS have been intensively studied recently. High density lipoprotein (HDL) is considered as one of the most important therapeutic target as it functions importantly in the AS and negatively correlates with the incidence. In this review, we would summarize the progress of the drug development targeting HDL, focusing on the feasibility and limitations. Moreover, we would also provide our perspectives in this field.