Significance Although exercise is a well known and potent stimulus for new bone formation, and weightlessness or muscle loss characteristically cause bone loss, it has remained unclear how muscle talks to bone, despite their close proximity. Here, we show that a molecule irisin derived from skeletal muscle in response to exercise has profound effects in enhancing mass and improving the geometry and strength specifically of cortical bone, the key function of which is to resist bending and torsion. Trabecular bone, which is a reservoir for bodily calcium, is remarkably spared. Irisin may therefore not only be the molecule responsible for muscle–bone connectivity, but could also become a therapy for sarcopenia and osteoporosis, which occur in tandem in the elderly.