Impact forces have been speculated to be associated with the development of musculoskeletal injuries. However, several findings indicate that the concepts of “impact forces” and the paradigms of their “cushioning” may not be well understood in relation to the etiology of running injuries and that complex mechanisms may be responsible for injury development during running. The purposes of this paper are (a) to review impact mechanics during locomotion, (b) to review injuries and changes of biological tissue due to impact loading, and (c) to synthesize the mechanical and biological findings. In addition, directions for future research are discussed. Future research should address the development of noninvasive techniques to assess changes in the morphology and biochemistry of bone, cartilage, tendon, and ligaments; researchers should also try to simulate impact loading during activities such as running, focusing on the interaction of the various loading parameters that determine the acceptable windows of loading for biological tissues.