Monoclonal antibodies (mAbs) and antibody-based fusion molecules have now come of age as therapeutics. Eighteen mAbs and two fusion molecules are on the market. mAbs directed against new targets are progressing at a rapid rate with the help of proteomics and genomics approaches. Many technical efforts have been made to generate a second-generation mAb with decreased immunogenicity and with optimised effector functions. The development of molecular engineering techniques applied to antibody molecules has also made it possible to design fusion molecules exhibiting different modules with bifunctional activities. Different approaches developed over the last two decades to generate and optimise therapeutic antibodies and antibody-based fusion molecules are described, with a particular focus on antibodies and fusion proteins used in oncology and inflammatory diseases. Some current technical challenges and trends are also discussed.