Repair machinery and local infection control failure contribute to wound chronicity and lower extremity amputation in diabetic patients. In these wounds, inflammation is a proximal condition which disrupts wound matrix turnover and the local redox balance. Contemporary therapeutic interventions are relatively broad including drugs, devices and surgical procedures. However, clinical efficacy remains modest and recurrences are frequent. Recombinant growth factors advent was followed by their premature and empiric introduction in the clinical practice. Its topical administration is still challenged by local kinetic and pharmacodynamic limitations related to the hostile microenvironment of chronic wounds. The rationale of infiltrating epidermal growth factor (EGF) down inside complex diabetic wounds as an alternative treatment modality is described here. The concept emerged from two experimental evidences: (a) locally infiltrated EGF prevented trophic ulcers and limb necrosis upon denervation, (b) acute, controlled experimental wounds' exudate exhibited proteolytic activity. Depositing EGF in deep cells' responsive strata allows for two main pharmacological actions indispensable for chronic wounds healing: cyto-protection and proliferation of fibroblasts and endothelial cells, thus inducing progressive granulation. Ten years of clinical experience have validated laboratory and theoretical concepts, while most importantly have improved quality-of-life to thousands of diabetic patients.