Mesenchymal stem cells (MSCs) are among the most promising and suitable stem cell types for vascular tissue engineering. Substantial effort has been made to differentiate MSCs towards vascular cell phenotypes, including endothelial cells and smooth muscle cells (SMCs). The microenvironment of vascular cells not only contains biochemical factors that influence differentiation, but also exerts hemodynamic forces, such as shear stress and cyclic strain. Recent evidence has shown that these forces can influence the differentiation of MSCs into endothelial cells or SMCs. In this Commentary, we present the main findings in the area with the aim of summarizing the mechanisms by which shear stress and cyclic strain induce MSC differentiation. We will also discuss the interactions between these mechanical cues and other components of the microenvironment, and highlight how these insights could be used to maintain differentiation.