<p>Wounds that exhibit delayed healing have a tremendous impact on health care expenditures and place patients at serious risk for severe complications including death. The healing of a chronic wound requires the restoration of multiple factors that normally work in concert to repair the damaged skin barrier. Skin substitutes have shown great promise for use as adjunctive therapies for refractory wounds by providing cells, soluble mediators, and extracellular matrix materials needed to stimulate healing. There are a growing variety of skin substitutes available on the market with many indications, and appropriate selection can impact healing outcomes. Skin substitutes can be broadly divided into cellular and acellular devices, yet within these categories, each product has its own unique composition and mechanism for promoting healing. Here we summarize the characteristics and indications of cellular and acellular matrices commonly used in wound care with the most evidence supported by randomized control trials and prospective studies. This review aims to provide dermatologists and other wound care clinicians with a helpful guide on how to approach skin substitutes, from preparing the wound bed for application, to making the proper selection for patients' individual wounds.</p> <p><em>J Drugs Dermatol. 2018;17(1):57-64.</em></p>.