The importance of this system is underscored by the complex repair mechanisms that have evolved to restore tissue integrity after injury. Wound repair requires the immediate activation of numerous overlapping pathways and cell types to synchronously clear debris, produce extracellular matrix , and revascularize the injured area. The enormous biomedical and financial burden of wounds emphasizes the importance of understanding the mechanisms governing wound healing and designing effective therapies to improve outcomes. Each injury, whether iatrogenic or traumatic in etiology, activates a common pathway of wound healing, where deposition of cells and ECM restores skin integrity. However, the deposited tissue is predominantly composed of fibroblasts and collagen, resulting in a patch of nonfunctional fibrotic tissue, known as scar. In contrast, injured fetal skin up to 6 months of gestation and some eukaryotic organisms retain the ability to regenerate skin with structure and function nearly identical to the original tissue [4,5]. This is likely due to the survival benefits associated with rapid restoration of tissue integrity, minimization of blood loss, and prevention of infection. The resulting scar possesses 80% of the tensile strength of innate skin and, if anatomically located in proximity to joints or orbits, may result in functional impairment as the scar contracts [6]. The mechanism of cutaneous wound healing with the resultant deposition of fibrotic tissue is similar to the response to injury found in tissue throughout the body. This chapter provides an overview of normal and impaired wound healing, highlights some of the clinical and research challenges, and describes current and developing therapies to improve the response to injury.