Fibrosis, which affects millions of individuals worldwide, is a leading cause of organ failure. For 40 years myofibroblasts have been recognized to be the key cellular players in fibrosis. Currently, several pharmaceutical targets are under investigation that may contribute to the activation of myofibroblasts. Recent preclinical and clinical evidence suggests that other components in the fibrotic microenvironment can trigger myofibroblast activation, providing new targets for pharmaceutical intervention. Epithelial cells may represent the most promising cellular phenotype that could be exploited in the design of new anti-fibrotic medicines through their paracrine action on myofibroblasts. The present review briefly highlights this hypothesis and discusses some interesting related pharmacological targets.