Organs-on-a-chip (OOAC) are research platforms containing cellular models designed to recapitulate relevant biological cues and, in some cases, enable communication between ‘on-chip’ connected organs. With enhanced physiological relevance, improvements in predictivity of the efficacy and toxicity of test compounds are anticipated. However, there are challenges to demonstrate the ‘gain of confidence’ of this technology for patient benefit. Translational challenges, the opportunities and deficiencies of the organ models, their intercommunication. and the platform technology are all issues to be resolved. Sensitive, real-time detection technologies and data-rich readouts are needed to understand OOAC biology. Thus, the validation of normal and disease biology on chip, and modelling to translate these data to patients, will help position this technology in mainstream drug discovery.