While recent advances have occurred in the field of prosthetic technology, there is still a need for a neuroprosthetic interface that permits high-fidelity prosthetic control to accurately replicate extremity movements. Peripheral nerve interfaces offer more intuitive prosthetic control by harnessing neural signals at a fascicular level. The direct application of electrodes to peripheral nerves is limited by device encapsulation, micromotion, and inevitable neural damage. To overcome these challenges, the regenerative peripheral nerve interface (RPNI) has been developed as a promising solution to enhance prosthetic control. During RPNI surgery, the end of a transected peripheral nerve is implanted into an autologous free skeletal muscle graft. The RPNI has demonstrated feasibility in transducing peripheral nerve signals from patients with upper limb amputations to control an artificial hand. In addition, by leveraging the physiological processes of nerve regeneration, muscle regeneration, and reinnervation, RPNIs have been shown to reduce postamputation pain, including neuroma pain and phantom limb pain. It can be used as a treatment for symptomatic neuromas or performed prophylactically at the time of limb amputation to reduce or eliminate postamputation pain. RPNI surgery is a safe, reliable, and reproducible technique that can be easily adopted across a variety of surgical specialties. This article describes the development, validation, and clinical application of the RPNI and discusses the surgical technique.