Hypertrophic scarring poses a clinically relevant problem as it can be cosmetically disfiguring and functionally debilitating. A lack of animal models has hindered an understanding of the pathogenesis and development of new treatment strategies therefore has largely been empiric. Our group has developed a unique hypertrophic scar (HS) model in the rabbit ear. The model has been reproducible, quantifiable, and measurable over a time period of 1 month. We describe the development as well as the reliability and responsiveness of this model to different therapeutic agents, such as TGF-beta blockade, silicone occlusion, and application of collagen-synthesis inhibitors. Moreover, it has given insights into the mechanism of action of silicone sheeting occlusive treatment and ultimately suggests that the epidermis plays a critical role in the development of HS. Additionally, we will present new data supporting the importance of the epidermis and further clarify the mechanism of action of silicone sheeting. When a semi-occlusive polyurethane film was left in place for an additional time period, scar formation was reduced. HSs of this model covered with silicone sheets and five layers of Tegaderm showed a significant scar reduction by 80% compared with wounds with only one layer of Tegaderm. The HS model in the rabbit ear is a highly reliable, responsive, and practical model for studying scar tissue behavior. Furthermore, our data suggest that the degree and the duration of occlusion are most important for reducing scar tissue formation.