In recent years, engineering biocompatible HDL nanodiscs has garnered a great interest with wide applications for both drug delivery and structural biology. In this review, we outline the exceptional advantages of nanodiscs for drug delivery research, including their ultrasmall size, extended circulation time, high stability, good tolerability and inherent tissue targeting properties. Besides their unique advantages, we also review the obstacles that can limit the use of nanodiscs as drug carriers. These challenges include the costly and laborious process of isolation and purification of endogenous HDL in addition to the production hurdles and the safety concerns linked to the conversion of HDL into nanoscale therapeutics loaded with drugs. We also explore the utility of nanodiscs in structural biology, focusing on their capability to allow for better investigation of the interactions between viruses and their corresponding receptors on cellular membranes as well as structural characterization of membrane proteins. Furthermore, we discuss the recent advancements and strategies developed to overcome the challenges associated with conventional nanodiscs, such as using recombinant ApoA1 proteins and ApoA1 mimetic peptides as alternatives to endogenous HDL. Lastly, we evaluate the potential for clinical translation and the promising future applications of nanodiscs.