Many complex, chronic, full-thickness wounds are unresponsive to traditional therapies. Acellular matrices have emerged as viable alternative treatments. Although limited, data confirm the safety and efficacy of acellular matrices, demonstrate their capacity to accelerate epithelialization, and validate their ability to increase the proportion of healed lower extremity wounds. The clinician must thoroughly understand differences between acellular matrices. Adequate vascular supply, debridement with eradication of infection, and offloading are critical in managing these wounds. Recent advances in acellular biologic tissue scaffolds are highlighted and discussed, and surgical techniques for applying regenerative tissue scaffolds to a variety of wound types are reviewed.