Synthetic antibody libraries, whose repertoires are designed, have advanced in the last decade to rival natural repertoire-based libraries. Many types of diversity design have been shown to generate highly functional libraries. Defined template and defined diversity in synthetic antibody libraries improve the process of discovering and optimizing new antibodies. Synthetic libraries with different diversity design have targeted different epitopes on antigens, including epitopes that are unlikely to be targeted by immunization and hybridoma. Cross-species binding antibodies are prime examples of products generated by synthetic antibody libraries, and they are becoming the tools of choice to validate the selection of targeted molecules in therapeutic development. Synthetic antibody libraries complement the existing natural repertoire-based antibody libraries and hybridoma approach to maximize the potentials of antibodies as therapeutics.