Exercise elicits an immunological "danger" type of stress and inflammatory response that, on occasion, becomes dysregulated and detrimental to health. Examples include anaphylaxis, exercise-induced asthma, overuse syndromes, and exacerbation of intercurrent illnesses. In dangerous exercise, the normal balance between pro- and anti-inflammatory responses is upset. A possible pathophysiological mechanism is characterized by the concept of exercise modulation of previously activated leukocytes. In this model, circulating leukocytes are rendered more responsive than normal to the immune stimulus of exercise. For example, in the case of exercise anaphylaxis, food-sensitized immune cells may be relatively innocuous until they are redistributed during exercise from gut-associated circulatory depots, like the spleen, into the central circulation. In the case of asthma, the prior activation of leukocytes may be the result of genetic or environmental factors. In the case of overuse syndromes, the normally short-lived neutrophil may, because of acidosis and hypoxia, inhibit apoptosis and play a role in prolongation of inflammation rather than healing. Dangerous exercise demonstrates that the stress/inflammatory response caused by physical activity is robust and sufficiently powerful, perhaps, to alter subsequent responses. These longer term effects may occur through as yet unexplored mechanisms of immune "tolerance" and/or by a training-associated reduction in the innate immune response to brief exercise. A better understanding of sometimes failed homeostatic physiological systems can lead to new insights with significant implication for clinical translation.