The effects of mechanical stability and mechanical stimulation have been studied extensively in vivo using a variety of animal models and stimulators. Early results indicated that stimulation does not significantly contribute to fracture healing. Lately, however, more rigid external stimulators that withstand increased callus formation have identified a contribution of mechanical stimulation in the initial period of fracture healing. However, these studies also show that the same amount of movement inhibits union during the last phase of fracture healing. On the cellular level, most investigations have used 2-dimensional cell culture systems to study the response of different cell phenotypes to mechanical stimulation, shear stress, and hydrostatic pressure. Cell proliferation and differentiation are clearly altered by these stimuli, however, the response depends on the cell type, the magnitude of the strain, and the cofactors applied. Lately, 3-dimensional cell cultures in mechano-bioreactors have been used to investigate the response of bone marrow stromal cells. These results indicate that the predominant stimulus for proliferation is perfusion. Mechanical stimulation affects cell differentiation and depends on the strain magnitude and the cell phenotype. As a consequence, today's implants should be applied in a fashion that supports maximum perfusion at the fracture site. In the early period, the osteosynthesis should facilitate micromotion of the fragments if secondary fracture healing is desired. At the same time, joint congruency, and axial and rotational positions have to be maintained. In the final period of healing, motion within the calcifying callus should be limited, which is naturally achieved by the increasing stiffness of the callus ossification.