Biophysical cues such as biomaterial nanoscale stiffness and biomechanical forces have emerged as essential determinants of cell fate, which can be equally important as biochemical and genetic factors. Acknowledging this, one uses terms such as the “rise of mechano-transduction”, “mechano-transduction: use the force”, and “mechano-transduction: may the force be with you”. These biophysical cues have in common that they modulate the balance between extracellular and intracellular forces, alter cytoskeleton stress and cellular shape, and, importantly, also the associated cell function. Prof. Rolauffs and his team have demonstrated that cell shape and function are controlled by biomaterial surface nanoscale stiffnesses and biomechanical forces such as cyclic stretch. In turn, they demonstrated that ranges of distinct cell shapes can intentionally be engineered by choosing specific stiffnesses and tensile forces. Dissecting these processes, Prof. Rolauffs and his team have set up a cell stimulation system, which combines two competing biophysical cues: cyclic stretch with dynamic effects on cell shape and nanoscale stiffness of the used biomaterial with static effects on cell shape. This unraveled that the biomechanical effects on cell shape were more effective than stiffness but the effects were also transient; ultimately, cell shape reverses back to the shape dictated by biomaterial properties. Moving forward, a promising application of this insight is to develop shape-instructive biomaterials that offer nanoscale cues and that transduce the dynamic in vivo biomechanical environment into specific MSC shapes for controlling MSC behavior.