The reconstruction of patients who possess multi morbid medical histories remains a challenge. With the ever-increasing number of patients with diabetes, infections, and trauma, there is a consistent need for promotion of soft tissue healing and a reliable substrate to assist with every aspect of soft tissue reconstruction, as well as the loss of fascial domain. Several proprietary products filled some of these needs but have failed to fulfill the needs of the clinician when faced with reconstructing multiple soft tissue systems, such as the integument and the musculoskeletal system. In this paper we discuss the use of decellularized human dermis (DermaPure®, Tissue Regenix, Universal City, TX, USA) through which a unique human tissue processing technique (dCELL® technology, Tissue Regenix, Universal City, TX, USA) and the creation of multiple product forms have proven to exhibit versatility in a wide range of clinical needs for successful soft tissue reconstruction. The background of human tissue processing, basic science, and early clinical studies are detailed, which has translated to the rationale for the success of this unique soft tissue substrate in orthoplastic reconstruction, which is also provided here in detail.