The development of therapeutic monoclonal antibodies over the last 35 years has led to the emergence of a new class of useful therapeutic molecules. These “first generation” antibodies have been obtained thanks to the conjugated and huge efforts of both academic and biotech researchers. About 30 monoclonal antibodies are currently approved for therapeutic use in Europe, USA, and China. Strikingly, only a restricted number of these antibodies are immunoglobulin fragments, single variable domains, or multiunit formats based on the engineering of immunoglobulin variable domains. In the present chapter, we will review the major steps of the therapeutic antibodies history and we will highlight the enormous potential of antibody fragments, either used as multiunits such as bispecific antibodies, single units, or as cell modifiers such as intrabodies or cell surface-expressed molecules.