Abstract Upper-limb prosthetic devices demand high performance technology to work hand in hand with human body for replacing one of the most delicate “tools” of nature, the human hand. In this chapter, we try to highlight the foundational elements, advancements and challenges for moving to high performance control of many-degrees-of-freedom upper-limb prostheses. As expected, the advances span across many different areas of engineering (robotics, sensors, control, and nanotechnology), biology, and medicine.