Since the first description of multiple sclerosis (MS) by Charcot, stress has been hypothesized to be a potential trigger of relapses. In recent years, data from observational studies in MS patients have provided some support for an association between stress and MS relapses. Furthermore, studies employing the MS animal model experimental autoimmune encephalomyelitis have shown that certain stressors can exacerbate the disease if administered prior to disease induction. Several lines of research have explored the 2 major stress response systems – the hypothalamic-pituitary-adrenal axis and the autonomic nervous system – and their relation to disease course in MS and experimental autoimmune encephalomyelitis. These studies provide evidence that insensitivity of the immune system to signals from these systems may play a role in inflammatory events. These findings can be integrated into a biological model of stress response system alterations in MS.