The body’s main stress axis, the hypothalamic-pituitary–adrenal (HPA) axis, has profound effects on growth and immune function that can impact health well into adulthood. In the short term, elevations in cortisol, the main stress hormone in humans, promote a catabolic state to allow for short-term defense against stressors that may be psychological or physiological in nature. In the long term, however, elevations in glucocorticoids from either endogenous or exogenous sources promote reductions in bone mass, bone density, stature, muscle mass, and an increase in central adipose gain in children and adolescents. These deleterious effects can also set the stage for numerous chronic diseases. Exercise is a potent activator of the HPA axis in humans and in rodents, yet regular exercise is not associated with chronic elevations in circulating GCs or the detrimental effects of elevated GCs, likely because of several adaptations to the HPA axis. In some cases of excessive exercise and overtraining, the detrimental effects of chronic elevations in GC levels that impact normal growth can be observed. The cellular, molecular, and physiological interactions of exercise, stress, and immune function in the context of normal and abnormal growth are highlighted in this chapter.