It has been suggested that physical trauma, involving the cervical spinal cord or the brain, and psychological stress may precede MS onset or may influence the disease course, although this hypothesis has mainly come from anecdotal case reports or small uncontrolled or controlled studies. So far there are no studies providing a clear causative relationship between physical trauma (especially head trauma) and MS onset, exacerbation or progression of the disease. On the other hand, recent MRI and experimental studies, supporting the important role of nervous and immune system interactions, particularly by the hypothalamic-pituitary-adrenal axis and by the sympathetic nervous pathways, seem to demonstrate a significant correlation between stress and MS exacerbations. Further frequent MRI and immunological evaluations should be warranted to objectively document the temporal association between stress and clinical and/or sub-clinical disease activity.