Background: Currently, no biological assay exists to objectively assess wounds to aid in timing of wound closure and guide therapy. In this article, the authors review military investigations in biomarkers as a method of objectively determining acute traumatic wound physiology and their applicability in predicting healing of complex soft-tissue wounds. Methods: The civilian literature related to biomarkers and wound physiology related to chronic and acute wounds was reviewed as a basis for current research into acute traumatic soft-tissue wounds. Results: Analysis of serum and wound effluent from traumatic extremity soft-tissue combat wounds revealed changes in specific proinflammatory matrix metalloproteinases associated with impaired wound healing. Forsberg et al. analyzed serum and wound effluent for chemokines and cytokines. An increase in serum procalcitonin levels correlated with wound dehiscence. Lastly, serum, wound effluent, and wound bed tissue biopsy specimens were analyzed by Hawksworth et al. Consistent with previous studies, elevation in proinflammatory cytokines was associated with wound dehiscence. Conclusions: Changes in levels of proteases, protease inhibitors, and inflammatory markers have been correlated with wound healing. These findings further support the idea that inflammatory dysregulation and a persistent inflammatory state leads to failure of wound healing in the acute setting. These findings highlight potential targets for the development of a biological assay to individualize management of complex soft-tissue wounds, based on patient physiology and response, that would be applicable to not only military trauma but also civilian trauma. Ultimately, this would result in earlier wound closure, reduction in the number of operating room trips, and reduced health care costs.