PURPOSE OF REVIEW: Summarize the initial discovery of discoidal high-density lipoprotein (HDL) in human plasma and review more recent innovations that span the use of reconstituted nanodisc HDL for membrane protein characterization to its use as a drug carrier and a novel therapeutic agent for cardiovascular disease. RECENT FINDINGS: Using a wide variety of biophysical techniques, the structure and composition of endogenous discoidal HDL have now largely been solved. This has led to the development of new methods for the in vitro reconstitution of nanodisc HDL, which have proven to have a wide variety of biomedical applications. Nanodisc HDL has been used as a platform for mimicking the plasma membrane for the reconstitution and investigation of the structures of several plasma membrane proteins, such as cytochrome P450s and ABC transporters. Nanodisc HDL has also been designed as drug carriers to transport amphipathic, as well as hydrophobic small molecules, and has potential therapeutic applications for several diseases. Finally, nanodisc HDL itself like native discoidal HDL can mediate cholesterol efflux from cells and are currently being tested in late-stage clinical trials for cardiovascular disease. The discovery of the characterization of native discoidal HDL has inspired a new field of synthetic nanodisc HDL, which has offered a growing number of unanticipated biomedical applications.