Bispecific antibodies (bsAbs) have been on the scene for decades and represent the next generation of antibody-based therapeutics. Unlike monospecific, monoclonal antibodies (mAbs), bsAbs can target two or more disease mechanisms as a single agent and can offer certain unique therapeutic strategies that are difficult to acheive with mAbs. The lessons learned during the past 35 years of mAb development and 25 years of bsAbs experience are shaping development of the next generation of bsAbs and multispecific antibody-based drugs. Recent improvements in manufacturability and drug-like properties of certain BsAb formats, and clinical success for a few BsAbs, are reviving this area. In this article, we discuss the potential limitations of the first-generation mAbs and opportunities to improve upon existing mAb drugs, factors driving the multispecific antibody field and the strengths, weaknesses and development status of representative multispecific antibody concepts.