Background: Chronic wounds, especially in patients with diabetes, oftenrepresent clinical challenges. Recently the use of a topically applied blood clot has garnered significant interest. This stromal matrix contains viable cells that are autologous, biocompatible, biological and consistent with a metabolically active scaffold. It has been shown to be safe, effective, and cost efficient. However, the mechanism of action of this modality remains elusive. The objective of this manuscript is to identify a potential mechanism of action of an autologous blood clot.Methods: Review of clinical and scientific literature hypothesizes on how autologous blood clots may stimulate healing and facilitate the movement of critical substrates while lowering bioburden and fostering angiogenesis.Results: Blood serves as a carrier for many components: red blood cells, white blood cells, platelets, proteins, clotting factors, minerals, electrolytes, and dissolved gasses. In response to tissue injury, the hemostatic mechanism employs a host of vascular and extravascular responses initiating primary, secondary, and tertiary hemostasis. The scaffold created by the autologous blood clot tissue provides a medium in which the body can transform the wound from a non-healing chronic condition into a healing "acute" condition. The autologous blood clot tissue also creates a protective setting for the body to utilize its own mechanisms to promote wound healing in an organized manner. This transient scaffold recruits surrounding fibroblasts and promotes cell ingrowth to foster granulation tissue remodeling. Cells in this matrix not only sense soluble factors, but also their physical environments. This well-orchestrated mechanism includes signals from soluble molecules, from the substrate/matrix to which the cell is adherent, from the mechanical or physical forces acting on it, and from contact with other cells. Topically applied autologous blood clot tissue can lower bacterial bioburden while stimulating angiogenesis and fostering the movement of keratinocytes and fibroblasts.Conclusions: Topically applied autologous blood clot tissue represents a formidable cellular and tissue based therapy that has been shown to be safe and effective. Although the central component of this therapy is blood, the autologous clot tissue creates a scaffold that performs as a biologic delivery system that functions to control the release of growth factors and cytokines over several days.