Glioblastomas are high-grade brain tumours with a poor prognosis and, currently, few available therapeutic options. This lack of effective treatments has been linked to diverse factors, including target selection, tumour heterogeneity and poor penetrance of therapeutic agents through the blood-brain barrier and into tumours. Therapies using monoclonal antibodies, alone or linked to cytotoxic payloads, have proved beneficial for patients with different solid tumours; these approaches are currently being explored in patients with glioblastoma. In this Review, we summarise clinical data regarding antibody-drug conjugates (ADCs) against a variety of targets in glioblastoma, and compare the efficacy and toxicity of targeting EGFR with ADCs versus naked antibodies in order to illustrate key aspects of the use of ADCs in this malignancy. Finally, we discuss the complex challenges related to the biology and mutational changes of glioblastoma that can affect the use of ADC-based therapies in patients with this disease, and highlight potential strategies to improve efficacy.