Mechanical forces are important signals in the development and function of the heart and lung, growth of skin and muscle, and maintenance of cartilage and bone. The specific mechanical force "shear stress" has been implicated as playing a critical role in the physiological responses of blood vessels through endothelial cell signaling. More recently, studies have shown that shear stress can induce differentiation of stem cells toward both endothelial and bone-producing cell phenotypes. This review will highlight current data supporting the role of shear stress in stem cell fate and will propose potential mechanisms and signaling cascades for transducing shear stress into a biological signal. 0 2009 American Institute of Chemical Engineers Biotechnol. Prog., 25: 10-19, 2009