In vitro gait simulations have been available to researchers for more than two decades and have become an invaluable tool for understanding fundamental foot–ankle biomechanics. This has been realised through several incremental technological and methodological developments, such as the actuation of muscle tendons, the increase in controlled degrees of freedom and the use of advanced control schemes. Furthermore, in vitro experimentation enabled performing highly repeatable and controllable simulations of gait during simultaneous measurement of several biomechanical signals (e.g. bone kinematics, intra-articular pressure distribution, bone strain). Such signals cannot always be captured in detail using in vivo techniques, and the importance of in vitro experimentation is therefore highlighted. The information provided by in vitro gait simulations enabled researchers to answer numerous clinical questions related to pathology, injury and surgery. In this article, first an overview of the developments in design and methodology of the various foot–ankle simulators is presented. Furthermore, an overview of the conducted studies is outlined and an example of a study aiming at understanding the differences in kinematics of the hindfoot, ankle and subtalar joints after total ankle arthroplasty is presented. Finally, the limitations and future perspectives of in vitro experimentation and in particular of foot–ankle gait simulators are discussed. It is expected that the biofidelic nature of the controllers will be improved in order to make them more subject-specific and to link foot motion to the simulated behaviour of the entire missing body, providing additional information for understanding the complex anatomical structure of the foot.