Increasing numbers of studies are reporting an association between stressful life events and exacerbation in multiple sclerosis. We review findings that begin to suggest psychological, social and biological factors that may be involved in this relationship. Depression, negative attributions, poor coping, and low social support have been implicated as aggravating the relationship between stress and exacerbation. A model of glucocorticoid resistance on immune cells is also presented as one potential biological mechanism. It is emphasized that to date there is no evidence of causal relationships. It is argued that a purely causal relationship, in which stressful events alone trigger exacerbation, is unlikely. Rather, we propose that stress may be one factor among many that influence risk of exacerbation.