Chronic stress can accelerate age-related damage to the hippocampus. Adrenal glucocorticoids are thought to be responsible for this damage because of their ability to compromise energy metabolism and make neurons more vulnerable to glutamate excitotoxicity. Additional mechanisms by which stress or glucocorticoids could damage the hippocampus are considered in the context of recent evidence that stress regulates neurotrophic factor expression in the brain. Stress has been found to decrease brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus, and this may contribute to stress-induced damage in this and other brain areas. Nerve growth factor (NGF) and neurotrophin-3 (NT-3) are increased by stress and glucocorticoids perhaps as a compensatory response to stress-induced damage. Because neurotrophic factors can protect the brain from a variety of traumatic insults, it is likely that they might also be effective in preventing or reversing glucocorticoid-induced damage to the hippocampus.