Human-centered design of wearable robots involves the development of innovative science and technologies that minimize the mismatch between humans’ and machines’ capabilities, leading to their intuitive integration and confluent interaction. Here, we summarize our human-centered approach to the design of closed-loop brain-machine interfaces (BMI) to powered prostheses and exoskeletons that allow people to act beyond their impaired or diminished physical or sensory-motor capabilities. The goal is to develop multifunctional human-machine interfaces with integrated diagnostic, assistive and therapeutic functions. Moreover, these complex human-machine systems should be effective, reliable, safe and engaging and support the patient in performing intended actions with minimal effort and errors with adequate interaction time. To illustrate our approach, we review an example of a user-in-the-loop, patient-centered, non-invasive BMI system to a powered exoskeleton for persons with paraplegia. We conclude with a summary of challenges to the translation of these complex human-machine systems to the end-user.