Similar to physical fitness, fitness of the immune system requires training. Animals that have been raised under sterile conditions have a poor immune system and fail to thrive. "Immune training" is normally provided by contact with live microorganisms or immunizations. Increasing evidence has suggested that moderate sports can decrease the frequency of infections while excessive, exhausting exercise can lead to the opposite, a situation that has been described by a J-curve. Following prolonged exhausting exercise, a transient partial suppression of several immune functions can be shown, and it has been suggested that this period provides a window for invasion of microbes. On the basis of data showing that endotoxin-inducible interferon-gamma (IFN-gamma) production is virtually abrogated for a short period following excessive exercise, we present the hypothesis that the rigorous regulatory blockade of one of the ways of IFN-gamma induction may be critically involved in causing the transient immunosuppression following exhaustive exercise stress.