Dynamic stresses that are present in all living tissues drive small fluid flows, called interstitial flows, through the extracellular matrix. Interstitial flow not only helps to transport nutrients throughout the tissue, but also has important roles in tissue maintenance and pathobiology that have been, until recently, largely overlooked. Here, we present evidence for the various effects of interstitial flow on cell biology, including its roles in embryonic development, tissue morphogenesis and remodeling, inflammation and lymphedema, tumor biology and immune cell trafficking. We also discuss possible mechanisms by which interstitial flow can induce morphoregulation, including direct shear stress, matrix-cell transduction (as has been proposed in the endothelial glycocalyx) and the newly emerging concept of autologous gradient formation.