The clinical application of monoclonal antibodies (mAbs) revolutionised the field of cancer therapy as it enabled the successful treatment of previously untreatable types of cancer. Different mechanisms play a role in the anti-tumour effect of mAbs and both target engagement with the Fab arm as well as Fc-mediated effector functions contribute to the efficacy of treatment. Because Ig isotypes differ in their ability to bind to FcRs on immune cells as well as in their ability to activate complement, they differ in the immune responses they activate. Therefore, the choice of antibody isotype for therapeutic mAbs is dictated by its intended mechanism of action. Considering that clinical efficacy of many mAbs is currently achieved only in subsets of patients, optimal isotype selection and Fc optimisation during antibody development may represent an important step towards improved patient outcome. Here, we discuss the current knowledge of the therapeutic effector functions of different isotypes and Fc-engineering strategies to improve mAbs application.