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Interleukin (IL)-6 can prevent or promote cancer development, depending on the context. IL-6 is released from skeletal muscles during exercise. IL-6 is also secreted by leukocytes and stromal cells at sites of inflammation and in the tumour microenvironment. Muscle-derived IL-6 enhances insulin sensitivity in glycogen-storing tissues, stimulates the appearance of anti-inflammatory cytokines in the blood, mobilises cytotoxic immune cells, and reduces DNA damage in cancer cells. These biological effects may help protect against cancer formation and progression. By contrast, sustained IL-6 signalling at sites of inflammation and in the tumour microenvironment promotes chronic low-grade inflammation and activates tumour-promoting signalling pathways. Interleukin (IL)-6 elicits both anticancer and procancer effects depending on the context, which we have termed the 'exercise IL-6 enigma'. IL-6 is released from skeletal muscles during exercise to regulate short-term energy availability. Exercise-induced IL-6 provokes biological effects that may protect against cancer by improving insulin sensitivity, stimulating the production of anti-inflammatory cytokines, mobilising immune cells, and reducing DNA damage in early malignant cells. By contrast, IL-6 continuously produced by leukocytes in inflammatory sites drives tumorigenesis by promoting chronic inflammation and activating tumour-promoting signalling pathways. How can a molecule have such opposing effects on cancer? Here, we review the roles of IL-6 in chronic inflammation, tumorigenesis, and exercise-associated cancer prevention and define the factors that underpin the exercise IL-6 enigma. [ABSTRACT FROM AUTHOR]