Stem cell research has opened new and exciting possibilities in the biological and biomedical sciences, and holds great promise of impacting many areas of medicine. However, despite the rapid advancements of the last decade, the precise and efficient differentiation of stem cells into distinct cell types and tissues still remains a major challenge for the field. In an effort to reproduce biologically relevant differentiation niches, or to direct stem cell differentiation into specific cellular fates, many investigators have explored the effect of biomechanical stimulation on pluripotent cells. This review focuses on a particular type of biomechanical force, namely fluid shear stress, and our current knowledge on its ability to direct differentiation and modulate function of embryonic and somatic stem cells.