Significance: Chronic wounds remain a significant public health problem. Alterations in normal physiological processes caused by aging or diabetes lead to impaired tissue repair and the development of chronic and nonhealing wounds. Understanding the unique features of the wound environment will be required to develop new therapeutics that impact these disabling conditions. New drug-delivery systems (DDSs) may enhance current and future therapies for this challenging clinical problem. Recent Advances: Historically, physical barriers and biological degradation limited the efficacy of DDSs in wound healing. In aiming at improving and optimizing drug delivery, recent data suggest that combinations of delivery mechanisms, such as hydrogels, small molecules, RNA interference (RNAi), as well as growth factor and stem cell-based therapies (biologics), could offer exciting new opportunities for improving tissue repair. Critical Issues: The lack of effective therapeutic approaches to combat the significant disability associated with chronic wounds has become an area of increasing clinical concern. However, the unique challenges of the wound environment have limited the development of effective therapeutic options for clinical use. Future Directions: New platforms presented in this review may provide clinicians and scientists with an improved understanding of the alternatives for drug delivery in wound care, which may facilitate the development of new therapeutic approaches for patients.