The reason that many proteins adopt a particular oligomeric form is far from obvious. In this chapter, we discuss potential advantages of proteins self‑assembling into specific quaternary structures. A number of case studies are presented in which wild‑type proteins have been mutated to generate variants of lower oligomeric order and the impact on the resulting proteins, in terms of both specific function and generic stability, are discussed. Drawing on these case studies, some general design principles for quaternary structure engineering are put forward to facilitate these experiments on a wider range of systems. It is clear that the advantages afforded by quaternary structure vary from protein to protein; however, some general trends are starting to emerge.