It was established that stem cells could repair lost endothelial cells and participate in the formation of neointimal lesions, because stem cells can differentiate into a variety of cells to replace dead cells or to repair damaged tissues. In this process, stem cells homing to the surface of injured vessels have to differentiate into vascular cells to exert their repairing functions (Xu Q. Circ Res. 2008;102:1011). Obviously, microenvironment where stem cells are attached play a crucial role in cell differentiation, although the spectrum of the initiators/stimulators responsible for such a differentiation remain to be clarified. It is well known that atherosclerotic lesions in the arteries are localized in some areas where blood flow is disturbed resulting in endothelial dysfunction/death in the presence of hyperlipidemia. Since recent findings suggest the potential role of stem cells in endothelial regeneration, it can be hypothesized that mechanical stress induced by blood flow can influence the differentiation process of stem cells (Xu Q. Nature Clin. Pract. Cardiovasc. Med. 2006;3:94). Support this hypothesis is recent findings that shear stress can induce differentiation of stem cells towards endothelial cell phenotype (Zeng et al. J Cell Biol. 2006; 174:1059), while stretch stress leads to differentiate into smooth muscle cells. It indicates that “good” blood flow (laminar shear stress) promotes endothelial differentiation from stem cells that tethering the surface of the vessel wall. How the stem cells sense and transduce the extracellular physical stimuli into intracellular biochemical signals is a crucial issue for understanding the mechanisms of stem cell differentiation. Collecting data derived from our and other laboratories showed that many kinds of molecules in the cells such as receptors, G proteins, cell cytoskeleton, kinases and transcriptional factors could serve as mechanoceptors directly or indirectly in response to mechanical stimulation implying that the activation of mechanoreceptors existing on the surface of stem cells is a crucial event. The sensed signals can be further sorted and/or modulated by processing of the molecules both on the cell surface and by the network of intracellular signalling pathways resulting in a sophisticated and dynamic set of cues that enable stem cell responses. The new findings indicate that signal pathway VEGF-Akt-HDAC-p53/p21 is crucial for stem cell differentiation into endothelial cells. The present presentation will summarize the data on shear stress-induced stem cell differentiation and the impact of such a differentiation on the pathogenesis of vascular diseases.