The preferred extracellular acceptor of cell phospholipids and unesterified cholesterol in the process mediated by the ATP-binding cassette A1 (ABCA1) transporter is a monomolecular, prebeta-migrating, lipid-poor or lipid-free form of apolipoprotein (apo) A-I. This monomolecular form of apoA-I is quite distinct from the prebeta-migrating, discoidal high-density lipoprotein (HDL) that contains two or three molecules of apoA-I per particle and which are present as minor components of the HDL fraction in human plasma. The mechanism of the ABCA1-mediated efflux of phospholipid and cholesterol from cells has been studied extensively. In contrast, much less attention has been given to the origin and subsequent metabolism of the acceptor lipid-free/lipid-poor apoA-I. There is a substantial body of evidence from studies conducted in vitro that a monomolecular, lipid-free/lipid-poor form of apoA-I dissociates from HDL during the remodeling of HDLs by plasma factors such as cholesteryl ester transfer protein, hepatic lipase, and phospholipid transfer protein. The rate at which apoA-I dissociates from HDL is influenced by the phospholipid composition of the particles and by the presence of apoA-II. This review describes current knowledge regarding the formation, metabolism, and regulation of monomolecular, lipid-free/lipid-poor apoA-I in plasma.