Exercise reduces the risk of a multitude of disorders, from metabolic disease to cancer, but the molecular mechanisms mediating the protective effects of exercise are not completely understood. The realization that skeletal muscle is an endocrine organ capable of secreting proteins termed 'myokines', which participate in tissue crosstalk, provided a critical link in the exercise–health paradigm. However, the myokine field is still emerging, and several challenges remain in the discovery and validation of myokines. This Review considers these challenges and highlights some recently identified novel myokines with the potential to be therapeutically exploited in the treatment of metabolic disease and cancer.