The goal of this review is to explain how to design a biomaterial approach to control the adaptive response to injury, with an emphasis on skin wounds. The strategies will be selected based on whether they have a reasonable probability of meeting the desired clinical outcome vs. just comparing the pros and cons of different strategies. To do this, the review will look at the normal adaptive response in adults and why it does not meet the desired clinical outcome in most cases. In addition, the adaptive response will be looked at in cases where it does meet the clinical performance requirements including animals that regenerate and for fetal wound healing. This will lead to how biomaterials can be used to alter the overall adaptive response to allow it to meet the desired clinical outcome. The important message of the review is that you need to use the engineering design process, not the scientific method, to design a clinical treatment. Also, the clinical performance requirements are functional, not structural. The last section will give some specific examples of controlling the adaptive response for two skin injuries: burns and pressure ulcers. For burns, it will cover some preclinical studies used to justify a clinical study as well as discuss the results of a clinical study using this system. For pressure ulcers, it will cover some preclinical studies for two different approaches: electrical stimulation and degradable/regenerative scaffolds. For electrical stimulation, the results of a clinical study will be presented.