Abstract: The hypothalamic-pituitary-adrenal (HPA) axis and the proinflammatory cytokines (and interleukin-6 [IL-6] in particular) are enmeshed in the response to somatic stress, either in health or in acute or chronic disease. Usually IL-6 is elevated in states of septic (such as sepsis) or aseptic inflammation (such as rheumatoid arthritis). Exercise is a form of somatic stress. Local tissue IL-6 elevation is noted during shorter and less intense exercise, whereas brief peripheral IL-6 “bursts” are observed with longer and more intense exercise. Therapeutic interventions that target IL-6 or its soluble receptor are currently assessed, with an emphasis on autoimmune diseases and inflammatory conditions.