WHAT IS KNOWN AND OBJECTIVE: It is 20 years since the US Food and Drug Administration approved the first successful monoclonal anticancer antibody, trastuzumab. The therapeutic utility of monoclonal antibodies in cancer is often limited by partial clinical responses and the development of tumour resistance. An expanding strategy, to be reviewed here, to overcome the limited response and resistance to monotherapy utilizes concurrent treatment with two synergistic monoclonal antibodies. COMMENT: Key examples include two monoclonal antibodies, each engaging a distinct site of human epidermal growth factor receptor 2 (HER2), in the treatment of breast cancer and a combination of antibodies to two distinct T-cell antigens for the treatment of melanoma. Here, we provide an overview of the rationale and evidence for using selected monoclonal antibodies in combination for treating some cancers, along with potential hazards, especially autoimmune-related toxicities. WHAT IS NEW AND CONCLUSION: Thorough research, the development of panels of biomarkers and individualization of therapy will be necessary to optimize the use of these combinations and minimize the substantial risk of overstimulating the immune system.