Therapeutic proteins play a crucial role in modern healthcare. However, the rapid clearance of proteins in the circulation system poses a significant threat to their therapeutic efficacy. The generation of anti-drug antibodies expedites drug clearance, resulting in another challenge to overcome in protein delivery. Several methods to increase the circulation half-lives of these proteins and to minimize their immunogenicity have been developed. This Review discusses the causes of protein clearance in the body, evaluates the FDA-approved strategies to prolong protein circulation, and highlights recent progress in the field. Additionally, the strengths and drawbacks of these methods and our perspectives for advancing protein delivery are provided.