Neurologic diseases are often accompanied by significant life stress and consequent increases in stress hormone levels. Glucocorticoid stress hormones are known to have deleterious interactions with neurodegenerative processes, and are hypersecreted in neurologic disorders as well as in comorbid psychiatric conditions, such as depression. This article highlights the state of our knowledge on mechanisms controlling activation and inhibition of glucocorticoid secretion, outlines signaling mechanisms used by these hormones in neural tissue, and describes how endogenous glucocorticoids can mediate neuronal damage in various models of neurologic disease. The article highlights the importance of controlling stress and consequent stress hormone secretion in the context of neurologic disease states.