During recent years, accumulating data have shown that muscle cells are able to produce and secrete several hundred myokines. The finding that muscles produce and release myokines provides a conceptual basis for understanding some of the molecular mechanisms underlying organ cross talk, including muscle–liver and muscle–fat cross talk. The myokine prototype is interleukin-6 (IL-6). During exercise, contracting skeletal muscles release IL-6. It seems that IL-6 works as an energy sensor and exerts both local and endocrine metabolic effects. Given that the skeletal muscle is the largest organ in the human body, the discovery of contracting muscle as a cytokine-producing organ opens for a whole new paradigm: If the endocrine function of the muscle is not stimulated through contractions, it will cause malfunction of several organs and tissues of the body.