Protein-based therapeutics has become one of the most rapidly growing and successful drug class in the clinic. However, there are still a number of key challenges that need to be addressed before the full therapeutic potential of protein drugs can be realized. Of note, many biologically active proteins have very short in vivo half-lives, a fact that has greatly hindered their clinical applications. Consequently, several different strategies including polyethylene glycol modification and fusion with Fc or albumin have been developed and implemented to prolong the serum half-life of protein therapeutics. Here we will focus on the recent advances in the development of Fc-based antibody fragments and domains and their potential use as novel half-life-extending fusion partners for protein therapeutics.