Synthetic polypeptides, the analogues of natural proteins, are important biomaterials that have found broad biomedical applications. Ring-opening polymerization of N-carboxyanhydrides offers a reliable way to prepare high-molecular-weight polypeptides in large scale with diverse side-chain functionalities. The past two decades have seen significant advances in the polypeptide field, with the development of various controlled polymerization methodologies, the deeper understanding on secondary structures, and the discovery of new assembly behaviors and applications. In this Perspective, we highlight several key advances in the chemical synthesis and materials application of synthetic polypeptides and discuss promising future directions in this area.