Scavenger receptor class B type I (SR-BI) is a high-affinity receptor for high-density lipoprotein (HDL). The primary role of this receptor is the selective uptake of HDLs in the liver through reverse cholesterol transport. SR-BI interacts with HDL to regulate lipid metabolism and affects various vascular cell functions involved in atherosclerosis (As). In addition, SR-BI is involved in the development of malignant tumors and infectious diseases. This article reviews the function and potential therapeutic targets of SR-BI in As, malignancies, and infectious diseases.