Protein-polymer conjugates are an important class of long-acting proteins, and they have been applied in the diagnosis and treatment of various serious diseases. However, due to the shortcomings of non-specificity, low yield, and potential immunogenicity in current PEGylation method, exploring new, efficient, and mild methods for preparing protein-polymer conjugates with well-defined structures and controllable functions is an important scientific issue in this field. In recent years, our research group and colleagues integrated the two technologies of “site-selective protein modification” and “in situ controlled polymerization”, proposing the concept of “site-selective in situ controlled polymerization (SICP)” to replace traditional PEGylation technology, and made great progress in biomedical applications. The research progress of SICP method is introduced in detail in this talk, which mainly focuses on the background of developing SICP methods, site-selective protein modification, in situ controlled polymerization, and the potential application of novel protein-polymer conjugates synthesized by SICP in the biomedical fields.