Understanding of the musculoskeletal system has evolved from the collection of individual phenomena in highly selected experimental preparations under highly controlled and often unphysiological conditions. At the systems level, it is now possible to construct complete and reasonably accurate models of the kinetics and energetics of realistic muscles and to combine them to understand the dynamics of complete musculoskeletal systems performing natural behaviors. At the reductionist level, it is possible to relate most of the individual phenomena to the anatomical structures and biochemical processes that account for them. Two large challenges remain. At a systems level, neuroscience must now account for how the nervous system learns to exploit the many complex features that evolution has incorporated into muscle and limb mechanics. At a reductionist level, medicine must now account for the many forms of pathology and disability that arise from the many diseases and injuries to which this highly evolved system is inevitably prone. © 2017 American Physiological Society. Compr Physiol 7:429-462, 2017.
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