Anti-PD-1/PD-L1 monoclonal antibodies have substantially improved the overall survival of a subset of patients across multiple solid tumour types, but other patients can have a deterioration of their disease as a result of such therapies. This paradoxical phenomenon is defined as hyperprogression. In this Review, we present the available evidence of hyperprogressive disease following immune-checkpoint inhibition, the pathophysiological hypotheses that might explain hyperprogressive disease and the current challenges for patient management in routine clinical settings. Finally, we also discuss how the risk of hyperprogressive disease should be taken into account in clinical decisions involving immune-checkpoint inhibition.