Since the first approval of recombinant human insulin three decades ago, more than 150 biopharmaceutical drugs have been marketed, and some of them became blockbuster drugs in market size. The patent expiration of the oldest biopharmaceutical drugs resulted in the development of biosimilar drugs. However the short serum half-life of biopharmaceutical drugs incurs a frequent injection to maintain a target clinical outcome in patients. The other major critical concern of biopharmaceutical drugs is immunogenicity producing anti-drug antibodies. These antibodies may reduce clinical efficacy by neutralizing biological activity, and may not only cause a severe allergic reaction but also other serious adverse reactions by blocking endogenous proteins. In order to improve pharmaceutical properties and reduce immunogenicity, the next generation biobetter drugs were achieved by glycoengineering technology, pegylation technology and protein engineering technology. Other biobetter drugs having optimized binding sites were also generated by in vitro display technology. Many of those biobetter drugs have been developed and/or are under development, and come into the clinical field in the near future.