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Significance: Shear stress controls multiple physiological processes in endothelial cells (ECs). Recent Advances: The response of ECs to shear has been studied using a range of in vitro and in viva models. Critical Issues: This article describes some of the experimental techniques that can be used to study endothelial responses to shear stress. It includes an appraisal of large animal, rodent, and zebrafish models of vascular mechanoresponsiveness. It also describes several bioreactors to apply flow to cells and physical methods to separate mechanoresponses from mass transport mechanisms. Future Directions: We conclude that combining in vitro and in vivo approaches can provide a detailed mechanistic view of vascular responses to force and that high-throughput systems are required for unbiased assessment of the function of shear-induced molecules. [ABSTRACT FROM AUTHOR]