The major constituents of soft tissues include cells, elastic and collagen fibers, and proteoglycans (PGs), a class of molecules that affect many processes including cell signaling, migration, mechanotransduction, matrix maintenance, and repair. This chapter presents examples and evidence that PGs have the ability to control molecular scale events with far-reaching consequences over multiple length scales ultimately influencing tissue structure in soft tissues such as tendon, skin, lung, vasculature, and cornea. The collagen-elastin network structure in turn determines macroscale function such as stiffness. This multiscale control of tissue structure and function occurs through myriad interactions involving PG core proteins and most prominently their highly charged glycosaminoglycan side chains. The lack or excess of these molecular scale interactions can cause a bifurcation in tissue growth, organization, and function culminating in disease. Exploiting their unique properties, PGs have the potential to advance tissue engineering and regenerative medicine approaches to solving human diseases.