Nine different antibody–drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of ADCs is to improve the therapeutic index of antineoplastic agents by restricting their systemic delivery to cells that express the target antigen of interest. Advances in synthetic biochemistry have ushered in a new generation of ADCs, which promise to improve upon the tissue specificity and cytotoxicity of their predecessors. Many of these drugs have impressive activity against treatment-refractory cancers, although hurdles impeding their broader use remain, including systemic toxicity, inadequate biomarkers for patient selection, acquired resistance and unknown benefit in combination with other cancer therapies. Emerging evidence indicates that the efficacy of a given ADC depends on the intricacies of how the antibody, linker and payload components interact with the tumour and its microenvironment, all of which have important clinical implications. In this Review, we discuss the current state of knowledge regarding the design, mechanism of action and clinical efficacy of ADCs as well as the apparent limitations of this treatment class. We then propose a path forward by highlighting several hypotheses and novel strategies to maximize the potential benefit that ADCs can provide to patients with cancer.