Exercise has beneficial effects in ameliorating metabolic disorders, and a combined therapeutic regimen of regular exercise and pharmaceutical treatment is often recommended. Exercise biology is complex and it involves various metabolic and molecular changes that translate into changes in substrate utilization, enzyme activation, and alternatively, improvement in exercise performance. Besides the effect of exercise on muscle metabolism, it has recently been discovered that contracting muscle can induce secretion of molecules called myokines. In the past few decades, a number of myokines have been discovered, such as interleukin-6, irisin, myostatin, interleukin-15, brain-derived neurotrophic factor, β-aminoisobutyric acid, meteorin-like, leukemia inhibitory factor, and secreted protein acidic and rich in cysteine, through secretome analysis. The existence of myokines has enhanced our understanding of how muscles communicate with other organs such as adipose tissue, liver, bone, and brain to exert beneficial effects of exercise at the whole body level. In this review, we focus on the role of these myokines in regulating local muscle metabolism as well as systemic metabolism in an autocrine/paracrine/endocrine fashion. The therapeutic potential of myokines and the natural or synthetic compounds known to date that regulate myokines are also discussed.