Skeletal muscle has been identified as an endocrine organ owing to its capacity to produce and secrete a variety of cytokines (myokines) and other proteins. To date, myokines have primarily been studied in response to exercise or metabolic challenges; however, numerous observations suggest that skeletal muscle may also release myokines in response to certain categories of internal or external stress exposure. Internal stress signals include oxidative or nitrosative stress, damaged or unfolded proteins, hyperthermia or energy imbalance. External stress signals, which act as indicators of organismal stress or injury in other cells, employ mediators such as catecholamines, endotoxin, alarmins, ATP and pro-inflammatory cytokines, such as tumour necrosis factor-α and interleukin-1β. External stress signals generally induce cellular responses through membrane receptor systems. In this review, we focus on the regulation of interleukin-6 (IL-6) as a prototypical stress response myokine and highlight evidence that IL-6 gene regulation in muscle is inherently organized to respond to a wide variety of internal and external stressors. Given that IL-6 can initiate protective, anti-inflammatory or restorative processes throughout the organism during life-threatening conditions, we present the argument that skeletal muscle has a physiological function as a sensor and responder to stress. Furthermore, we hypothesize that it may comprise a fundamental component of the organism's acute stress response.