Skeletal muscle works as a secretory organ with the capacity to produce hundreds of myokines. This finding provides a conceptual basis for understanding how muscles communicate with other organs such as adipose tissue, liver, pancreas, bones, and brain. The myokine IL-6 is released into the blood during exercise and it has been shown that IL-6 has multiple immunologic and metabolic effects. Here, we discuss recent advances regarding the physiology of IL-6. Human studies show that IL-6 infusion delays gastric emptying, reduces postprandial glucose concentrations and reduces insulin secretion, whereas experimental studies suggest a role for IL-6 in appetite regulation. Evidence is also accumulating for a central role of IL-6 in training-induced loss of visceral adipose tissue mass in humans. Moreover, recent experimental studies in mice show that voluntary exercise suppresses tumor growth through epinephrine-dependent and IL-6-dependent mobilization and redistribution of cytotoxic NK cells. It has been known for a while that IL-6 is a pleiotropic molecule; however, recent advances suggest that the physiological roles of IL-6 involve multiple aspects of metabolism as well as a role in tumor defense.