Advanced molecular biology techniques developed during the past few decades have allowed the industry to exploit and commercialize the natural defense mechanisms that antibodies provide. This review discusses the latest advances in antibody-engineering technologies to enhance clinical efficacy and outcomes. For the constant regions, the choice of the antibody class and isotype has to be made carefully to suit the therapeutic applications. Engineering of the Fc region, either by direct targeted mutagenesis or by modifying the nature of its N-glycan, has played an important role in recent years in increasing half-life or controlling effector functions. The variable regions of the antibody are responsible for binding affinity and exquisite specificity to the target molecule, which together with the Fc determine the drug's efficacy and influence the drug dose required to obtain the desired effectiveness. A key requirement during antibody development is therefore to affinity mature the variable regions when necessary, so that they bind the therapeutic target with sufficiently high affinity to guarantee effective occupancy over prolonged periods. If the antibody was obtained from a non-human source, such as rodents, a humanization process has to be applied to minimize immunogenicity while maintaining the desired binding affinity and selectivity. Finally, we discuss the next next-generation antibodies, such as antibody-drug conjugates, bispecific antibodies, and immunocytokines, which are being developed to meet future challenges.