Context:Skeletal muscle is comprised of a highly organized network of cells, neurovascular structures, and connective tissue. Muscle injury is typically followed by a well-orchestrated healing response that consists of the following phases: inflammation, regeneration, and fibrosis. This review presents the mechanisms of action and evidence supporting the effectiveness of various traditional and novel therapies at each phase of the skeletal muscle healing process.Evidence Acquisition:Relevant published articles were identified using MEDLINE (1978-2013).Study Design:Clinical review.Level of Evidence:Level 3.Results:To facilitate muscle healing, surgical techniques involving direct suture repair, as well as the implantation of innovative biologic scaffolds, have been developed. Nonsteroidal anti-inflammatory drugs may be potentially supplanted by nitric oxide and curcumin in modulating the inflammatory pathway. Studies in muscle regeneration have identified stem cells, myogenic factors, and β-agonists capable of enhancing the regenerative capabilities of injured tissue. Furthermore, transforming growth factor-β1 (TGF-β1) and, more recently, myostatin and the rennin-angiotensin system have been implicated in fibrous tissue formation; several antifibrotic agents have demonstrated the ability to disrupt these systems.Conclusion:Effective repair of skeletal muscle after severe injury is unlikely to be achieved with a single intervention. For full functional recovery of muscle there is a need to control inflammation, stimulate regeneration, and limit fibrosis.Strength-of-Recommendation Taxonomy (SORT):B