A neuroma occurs when a regenerating transected peripheral nerve has no distal target to reinnervate. This situation can result in a hypersensitive free nerve ending that causes debilitating pain to affected patients. No techniques to treat symptomatic neuromas have shown consistent results. One novel physiologic solution is the regenerative peripheral nerve interface (RPNI). RPNI consists of a transected peripheral nerve that is implanted into an autologous free skeletal muscle graft. Early clinical studies have shown promising results in the use of RPNIs to treat and prevent symptomatic neuromas. This review article describes the rationale behind the success of RPNIs and its clinical applications.