Few efficacious therapies exist for the treatment of fibrotic diseases, such as skin scarring, liver cirrhosis and pulmonary fibrosis, which is related to our limited understanding of the fundamental causes and mechanisms of fibrosis. Mechanical forces from cell-matrix interactions, cell-cell contact, fluid flow and other physical stimuli may play a central role in the initiation and propagation of fibrosis. In this Review, we highlight the mechanotransduction mechanisms by which various sources of physical force drive fibrotic disease processes, with an emphasis on central pathways that may be therapeutically targeted to prevent and reverse fibrosis. We then discuss engineered models of mechanotransduction in fibrosis, as well as molecular and biomaterials-based therapeutic approaches for limiting fibrosis and promoting regenerative healing phenotypes in various organs. Finally, we discuss challenges within fibrosis research that remain to be addressed and that may greatly benefit from next-generation bioengineered model systems.