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The major cardio-protective function of HDL is to remove excess cellular cholesterol in the process of HDL particle formation and maturation. The HDL biogenic procedure requiring protein–lipid interactions has been incompletely understood, and here we discuss recent progress and insights into the mechanism of HDL biogenesis.The initial and rate-limiting step of HDL biogenesis is the interaction between apoA-I and plasma membrane microdomains created by ATP-binding cassette transporter A1 (ABCA1) transporter. Computer simulation of molecular dynamics suggests that ABCA1 translocates phospholipids from the inner to the outer leaflet of the plasma membrane to create a transbilayer density gradient leading to the formation of an exovesiculated plasma membrane microdomain. The cryo-electron microscopy structure of ABCA1 suggests that an elongated hydrophobic tunnel formed by the extracellular domain of ABCA1 may function as a passageway to deliver lipids to apoA-I. In contrast to ABCA1-created plasma membrane microdomains, desmocollin 1 (DSC1) contained in a cholesterol-rich plasma membrane microdomain binds apoA-I to prevent HDL biogenesis. The identification of DSC1-containing plasma membrane microdomains as a negative regulator of HDL biogenesis may offer potential therapeutic avenues.Isolation and characterization of plasma membrane microdomains involved in HDL biogenesis may lead to a better understanding of the molecular mechanism of HDL biogenesis.