Since the identification of mutations in the ATP-binding cassette transporter (ABCA1), the relationship between ABCA1 expression, cholesterol efflux, high-density lipoprotein (HDL) biosynthesis and cholesterol homeostasis has been a subject of intense investigation. Several studies have provided significant new information with regards to pathways controlling ABCA1 expression and activity and established that this transporter facilitates the efflux of cholesterol and phospholipids to apoprotein acceptors, leading to the formation of nascent HDL particles. Although ABCA1 appears to play a critical role in cholesterol flux from tissues, and despite a considerable interest in developing pharmacological agents that increase ABCA1 activity, the role of ABCA1 in preventing atherosclerosis remains unclear.