Covalently conjugating proteins with synthetic polymers, particularly poly(ethylene glycol) (PEG) is widely used as a means to improve protein solubility and stability, prolong their circulating half-lives, and lower their immunogenicity. Conventionally, these polymers are attached to random locations on the protein surfaces through the modification of the reactive side chains of amino acid residues such as lysine and cysteine. The "grafting to" polymer conjugation usually leads to heterogeneous products with reduced activity and low yield, which may not be compatible with the intended applications. Therefore, it is highly desirable to synthesize well-defined protein polymer conjugates by site-specific polymer conjugation. Recently, in situ growth of polymer conjugates from proteins ("grafting from") has emerged as an alternative to the "grafting to" method. Particularly, site-specific in situ growth of polymer bioconjugates (SIP) is promising in overcoming the limitations of the "grafting to" method. In this review, we introduce the chemistry for synthesis of well-defined protein polymer conjugates, and emphasize the SIP method as the next-generation platform for synthesis of well-defined protein polymer conjugates. Furthermore, we exemplify biomedical applications of well-defined protein polymer conjugates. In the end, we come up potential directions in this research field. (C) 2015 Elsevier Ltd. All rights reserved.