Exercise has been recognized as a stress, which can significantly alter the host's immune response and, therefore, its susceptibility to disease. Whereas research in this area has previously focused primarily on human subjects and laboratory animals, it has more recently extended to domestic animals, especially the equine athlete. Despite several studies, defining the relationship among exercise, the immune response, and disease has proven difficult due to a number of factors, including the complexity of the immune system and the variable nature of exercise itself. It now appears that exercise has dual effects on the immune system. Suppressive effects, such as a decline in the ratio of CD4+ to CD8+ cells, diminished lymphocyte function, and a decline in the number and cytolytic activity of natural killer cells have been observed in response to brief high-intensity exercise, prolonged exhaustive exercise, and overtraining. In contrast, moderate training generally has beneficial effects on host defense mechanisms. The mechanisms for regulating the dual effects of exercise are complex, involving a network of neuroendocrine hormones and cytokines.