Physical activity offers protection against cardiovascular disease, type 2 diabetes. Physical training is also effective in the treatment of a number of medical disorders including ischemic heart disease, heart failure, chronic obstructive lung disease, type 2 diabetes and intermittent claudication. Although the beneficial effects of exercise are related somewhat to its positive effects on the lipid profile, insulin sensitivity and blood pressure, it is still unclear as to how muscle activity improves cardiovascular health. For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centres in exercise has been progressing. For lack of more precise knowledge, this stimulus has been called the ‘work stimulus’, ‘the work factor’ or ‘the exercise factor’. In other terms, one big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. In this talk, I suggest the possibility that interleukin-6 (IL-6) could mediate some of the beneficial health effects of exercise. In resting muscle, the IL-6 gene is silent, but it is rapidly activated by contractions. The transcription rate is very fast, the changes in muscle IL-6 mRNA are marked, and IL-6 is released from working muscles into the circulation in high amounts. IL-6 production is modulated by the glycogen content in muscles and, thus, IL-6 works as an energy sensor. IL-6 exerts its effect on adipose tissue, inducing lipolysis and gene transcription in abdominal subcutaneous fat and increases whole body lipid oxidation. Furthermore, IL-6 inhibits low-grade TNF-α-production and may thereby inhibit TNF-α-induced insulin resistance and contribute to an improvement in cardiovascular health. Thus, I suggest that IL-6 and other cytokines, which are produced and released by skeletal muscles, and which exert their effects in other organs of the body, should be named ‘myokines’.