In spite of the availability of six disease-modifying treatments for multiple sclerosis, a significant minority of patients fail to respond adequately to treatment. Switching immunomodulatory therapy is a potentially useful treatment strategy in such patients. Several factors contribute to the need to switch between immunomodulatory treatments, including the variable response to drug treatment, the timing and choice of therapy, disease severity, and the occurrence of neutralising antibodies. Guidelines have been proposed to define treatment response, integrating both clinical and imaging criteria. Several observational studies, principally evaluating a switch from beta-interferons to glatiramer acetate, have demonstrated that switching treatments is both safe and effective in patients with inadequate control of disease activity or who are experiencing unacceptable side effects with their original treatment. A treatment algorithm is proposed for decision-making when switching therapies appears warranted.