The introduction of newer therapies for the treatment of multiple sclerosis has generated considerable optimism. That optimism has been tempered by the potential risks of these therapies, such as the risk for progressive multifocal leukoencephalopathy. A review of the possible causes of reactivation of JC virus in this population has illustrated the need to better understand the untoward effects of monoclonal antibody therapies and other immunomodulatory therapies currently being contemplated for use in multiple sclerosis. These drugs alter the immune response at different sites, and most, if not all, affect more than one aspect of host immunity. Drawing from existing experience with the use of these immunomodulatory therapies in other conditions and that available from the limited experience with multiple sclerosis, we review their potential untoward effects. The latter include a predisposition to opportunistic and community-acquired infections, an altered response to vaccination, the development of cancers, and the appearance of autoimmune diseases. The identification of progressive multifocal leukoencephalopathy as a risk of therapy is relatively straightforward in light of its rarity and high morbidity and mortality, but a relatively slight increased risk for more common and less disabling disorders may be overlooked. Determining the actual risk frequency for many of these complications will likely require careful postmarketing surveillance. Ann Neurol 2009;65:367–377