Significance: Injuries to the skin as a result of illness or injury, particularly chronic nonhealing wounds, present a major healthcare problem. Traditional wound care approaches attempt to control the underlying causes, such as infection and ischemia, while the application of wound dressings aims to modify a poorly healing wound environment into a microenvironment more closely resembling an acute wound allowing the body to heal the wound naturally. Recent Advances: Regenerative medicine approaches, such as the use of biologic scaffold materials comprising an intact extracellular matrix (ECM) or individual components of the ECM, are providing new therapeutic options that focus upon the provision of biochemical cues that alter the wound microenvironment to facilitate rapid restoration of normal skin architecture. Critical Issues: The incidence of chronic nonhealing wounds continues to increase. For example, between 15% and 20% of diabetics are likely to develop chronic, nonhealing foot wounds creating an increasing burden on healthcare systems worldwide. Future Directions: Developing a thorough understanding of wound microenvironment and the mechanisms by which biologic scaffolds work in vivo has the potential to markedly improve outcomes in the clinical translation for the treatment of chronic wounds.