Symptomatic neuromas are a common cause of postamputation pain that can lead to significant disability. Regenerative peripheral nerve interface surgery is performed to treat symptomatic neuromas and prevent the development of neuromas. This review delineates the clinical problem of postamputation pain, describes the limitations of the available treatment methods, and highlights the need for an effective treatment strategy that leverages the biologic processes of nerve regeneration and muscle reinnervation. The evidence supporting use of regenerative peripheral nerve interface surgery to mitigate neuroma formation is discussed and the rationale behind the efficacy of regenerative peripheral nerve interfaces is explored.