Polypeptides derived from naturally occurring a-amino acids have emerged as a unique and versatile family of bio-inspired biomaterials that can be tailor-made for varying biomedical applications such as controlled drug release, gene delivery, tissue engineering and regenerative medicine. In contrast to traditional biodegradable polymers such as aliphatic polyesters and polycarbonates, polypeptides are inherently functional, allow precise control over polarity and charges, show excellent stability against hydrolysis, and are prone to rapid biodegradation in vivo by specific enzymes. Ring-opening polymerization (ROP) of alpha-amino acid N-carboxyanhydrides (NCAs) is the most straightforward and practical approach for large-scale production of high molecular weight polypeptides. In the past decade, a remarkable progress has been made in controlled NCA polymerization, which offers an unprecedented access to precision polypeptide and hybrid materials by combining with living radical polymerization, click chemistry, and/or post-polymerization modification. Notably, several micellar anti-cancer drugs based on poly(ethylene glycol)-polypeptides have been already advanced to the clinical evaluation. In this review paper, we give an overview on de novo design, controlled synthesis and emerging biomedical applications of functional polypeptide and hybrid materials. (C) 2013 Elsevier Ltd. All rights reserved.