Fibroblasts and myofibroblasts are found throughout mechanically loaded tissues, where they take primary responsibility for generating and maintaining the extracellular matrix scaffold upon which organ structure and function depends. They are thus tasked with creating the appropriate mechanical environment in which cells and tissues function optimally, and constantly adapting this environment as needed in response to changing environmental cues. To carry out these functions, fibroblasts must not only deposit and resorb the extracellular matrix, they must adhere to and sense its physical characteristics, and exert the forces necessary to shape, distort, and remodel it as desired. It is thus only through a constant reciprocal sensing and exertion of stress that fibroblasts can carry out their key functions. This introductory chapter will introduce these aspects of fibroblast stress sensing and matrix remodeling during tissue homeostasis, wound repair and fibrotic disease as a lead in to the detailed method chapters to follow on myofibroblast mechanobiology.