This chapter summarizes methods for the synthesis of polypeptides by ring-opening polymerization. Traditional and recently improved methods used to polymerize α-amino acid N-carboxyanhydrides (NCAs) for the synthesis of homopolypeptides are described. Use of these methods and strategies for the preparation of block copolypeptides and side-chain-functionalized polypeptides are also presented, as well as an analysis of the synthetic scope of different approaches. Finally, issues relating to obtaining highly functional polypeptides in pure form are detailed.