It has long been considered that fibrosis and fibroblast-to-myofibroblast differentiation are irreversible processes.However, recent data obtained indicates that tissue fibrosis and fibroblast-to-myofibroblast differentiation can indeed be reversed, which offers the possibility of a new therapeutic approach for fibrotic disorders.Here, we discuss the origin of the myofibroblasts and different aspects of their differentiation, especially the key mediators and TGFβ-induced signaling pathways.We also report here a few factors involved in myofiroblast dedifferentiation and several compounds which can reverse the established dedifferentiated myofibroblast, as examples that provide the reader a glimpse of the current trends of approach for discovering useful anti-fibrotic drugs.