Studies do not provide a consensus opinion of the relationship between stress and relapse in relapsing-remitting multiple sclerosis (RRMS). Few studies have defined the critical features of these stressful situations, or examined the role of stress-mediating and -moderating variables. Available evidence indicates that the relationship between life stress and relapse is complex, and is likely to depend on factors such as stressor chronicity, frequency, severity and type, and individual patient characteristics such as depression, health locus of control and coping strategy use. Little is known about how these factors, individually or in combination, are related to MS disease activity. Viral infections are also likely to precipitate relapse in MS, and significant life-stress may further enhance this relationship. The nature and strength of these interrelationships have strong clinical implications. MS patients are particularly vulnerable to a deteriorating cycle of stressful life events, illness episodes and disability. Timely multidisciplinary care interventions aimed at both minimizing psychological distress and physical symptoms may halt this downward reciprocal cycle. Little is known of the pathogenesis of these putative stress-induced changes in disease activity, and almost all stressor studies suffer from some biases or limitations.