Skeletal muscle is an endocrine organ that produces and releases myokines in response to contraction. Some myokines are likely to work in a hormone-like fashion, exerting specific endocrine effects on other organs such as the liver, the brain, and the fat. Other myokines will work locally via paracrine mechanisms, exerting, e.g., angiogenetic effects, whereas yet other myokines work via autocrine mechanisms and influence signaling pathways involved in fat oxidation and glucose uptake. The finding that muscles produce and release myokines creates a paradigm shift and opens new scientific, technological, and scholarly horizons. This finding represents a breakthrough within integrative physiology and contributes to our understanding of why regular exercise protects against a wide range of chronic diseases. Thus the myokine field provides a conceptual basis for the molecular mechanisms underlying, e.g., muscle-fat, muscle-liver, muscle-pancreas, and muscle-brain cross talk.