SMITH, L. L. Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? Med. Sci. Sports Exerc., Vol. 32, No. 2, pp. 317–331, 2000. Overtraining syndrome (OTS) is a condition wherein an athlete is training excessively, yet performance deteriorates. This is usually accompanied by mood/behavior changes and a variety of biochemical and physiological alterations. Presently, there is no global hypothesis to account for OTS. The present paper will attempt to provide a unifying paradigm that will integrate previous research under the rubric of the cytokine hypothesis of overtraining. It is argued that high volume/intensity training, with insufficient rest, will produce muscle and/or skeletal and/or joint trauma. Circulating monocytes are then activated by injury-related cytokines, and in turn produce large quantities of proinflammatory IL-1β, and/or IL-6, and/or TNF-α, producing systemic inflammation. Elevated circulating cytokines then co-ordinate the whole-body response by: a) communicating with the CNS and inducing a set of behaviors referred to as “sickness” behavior, which involves mood and behavior changes that support resolution of systemic inflammation; b) adjusting liver function, to support the up-regulation of gluconeogenesis, as well as de novo synthesis of acute phase proteins, and a concomitant hypercatabolic state; and c) impacting on immune function. Theoretically, OTS is viewed as the third stage of Selye’s general adaptation syndrome, with the focus being on recovery/survival, and not adaptation, and is deemed to be “protective,” occurring in response to excessive physical/physiological stress. Recommendations are made for potential markers of OTS, based on a systemic inflammatory condition.