One of the major failings in vascular tissue engineering is the limited capacity of autologous differentiated cells to reconstitute tissues. A logical solution is to use multipotent progenitor cells, which in vascular treatments have been underutilized. Although biochemical stimulation has been explored to differentiate bone marrow-derived progenitor cells (BMPCs) to smooth muscle cells (SMCs), the use of biomechanical forces in differentiation remains unexplored. The purpose of this work was to explore the effects of cyclic strain alone on BMPC morphology, proliferation, and differentiation. BMPCs were isolated from rat bone marrow and, after 7 days in culture, the cells grew in distinct multilayered colonies. BMPCs were stimulated with 10% strain at 1 Hz for 7 days. Observations showed that cyclic strain inhibited proliferation (p < 0.05) and caused alignment of the cells (p < 0.05) and of the F-actin cytoskeleton perpendicular to the direction of strain. In addition, cyclic strain resulted in expression by the cells of vascular smooth muscle a-actin and h1-calponin. This work demonstrates the potential of physiologic biomechanical stimulation in the differentiation of BMPCs to SMCs, and this could have important implications for vascular tissue engineering and other therapies in which cell sourcing is a major concern.