Schwann cells respond to nerve injury by cellular reprogramming that generates cells specialized for promoting regeneration and repair. These repair cells clear redundant myelin, attract macrophages, support survival of damaged neurons, encourage axonal growth, and guide axons back to their targets. There are interesting parallels between this response and that found in other tissues. At the cellular level, many other tissues also react to injury by cellular reprogramming, generating cells specialized to promote tissue homeostasis and repair. And at the molecular level, a common feature possessed by Schwann cells and many other cells is the injury-induced activation of genes associated with epithelial-mesenchymal transitions and stemness, differentiation states that are linked to cellular plasticity and that help injury-induced tissue remodeling. The number of signaling systems regulating Schwann cell plasticity is rapidly increasing. Importantly, this includes mechanisms that are crucial for the generation of functional repair Schwann cells and nerve regeneration, although they have no or a minor role elsewhere in the Schwann cell lineage. This encourages the view that selective tools can be developed to control these particular cells, amplify their repair supportive functions and prevent their deterioration. In this review, we discuss the emerging similarities between the injury response seen in nerves and in other tissues and survey the transcription factors, epigenetic mechanisms, and signaling cascades that control repair Schwann cells, with emphasis on systems that selectively regulate the Schwann cell injury response.