The interactions between lipids and proteins are one of the most fundamental processes in living organisms, responsible for critical cellular events ranging from replication, cell division, signaling, and movement. Enabling the central coupling responsible for maintaining the functionality of the breadth of proteins, receptors, and enzymes that find their natural home in biological membranes, the fundamental mechanisms of recognition of protein for lipid, and vice versa, have been a focal point of biochemical and biophysical investigations for many decades. Complexes of lipids and proteins, such as the various lipoprotein factions, play central roles in the trafficking of important proteins, small molecules and metabolites and are often implicated in disease states. Recently an engineered lipoprotein particle, termed the nanodisc, a modified form of the human high density lipoprotein fraction, has served as a membrane mimetic for the investigation of membrane proteins and studies of lipid–protein interactions. In this review, we summarize the current knowledge regarding this self-assembling lipid–protein complex and provide examples for its utility in the investigation of a large number of biological systems.