This perspective provides an overview of how risk can be effectively considered in physiological control loops that strive for semi-to-fully automated operation. The perspective first introduces the motivation, user needs and framework for the design of a physiological closed-loop controller. Then, we discuss specific risk areas and use examples from historical medical devices to illustrate the key concepts. Finally, we provide a design overview of an adaptive bidirectional brain-machine interface, currently undergoing human clinical studies, to synthesize the design principles in an exemplar application.