Amelogenin is an extracellular matrix protein with biological activity in the regeneration of the periodontium and repair of the skin. Recent published studies have highlighted the use of Xelma® (Mölnlycke Health Care AB, Göteborg, Sweden) in the treatment of hard-to-heal wounds, such as venous leg ulcers. This article reviews the literature relating to the cellular interactions of amelogenin and collates the clinical and health economic data relating to clinical and health economic studies involving patients with chronic wounds. It also discusses a hypothetical mechanism of action of amelogenin in the healing of such wounds.