The last years have seen enormous progress in our understanding of pathophysiology of multiple sclerosis. In addition, the armamentarium of available immunomodulatory or immunosuppressive therapies has greatly increased, especially for the relapsing remitting form of the disease. Since their therapeutic efficacy is often limited in individual patients, it is conceivable that combination therapies may bring improved clinical efficacy while managing increasing side effects and toxicity. The combination of agents with additive or synergistic modes of action is of particular interest. Combination of the two classes of recognised firstline treatment, a beta-interferon and glatiramer acetate is currently under evaluation in a large Phase III trial. However, there are theoretical reasons for thinking that such a combination may not be particularly beneficial. None of the combination studies performed with beta-interferons to date have shown unequivocal evidence of benefit, including combinations with statins, natalizumab and azathioprine. On the other hand, for glatiramer acetate, the combination with mitoxantrone used as induction therapy may be of interest and preliminary data on combination with minocycline are also promising.