Matrix synthesis, deposition and remodeling are complex biological processes that are critical in development, maintenance of tissue homeostasis and repair of injured tissues. Disturbances in the regulation of these processes can result in severe pathological conditions which are associated with tissue fibrosis as e.g. in Scleroderma, cutaneous Graft-versus-Host-Disease, excessive scarring after trauma or carcinogenesis. Therefore, finding efficient treatments to limit skin fibrosis is of major clinical importance. However the pathogenesis underlying the development of tissue fibrosis is still not entirely resolved. In recent years progress has been made unraveling the complex cellular and molecular mechanisms that determine fibrosis. Here we provide an overview of established and more recently developed mouse models that can be used to investigate the mechanisms of skin fibrosis and to test potential therapeutic approaches.