The availability of the second-generation therapies for relapsing multiple sclerosis (MS), natalizumab and fingolimod, provides new treatment options for MS but also presents new challenges. Both natalizumab and fingolimod appear to be more effective than the interferon beta products and glatiramer acetate, but both have more safety problems than do the first-generation therapies. Treatment with natalizumab is associated with a significant risk of patients developing progressive multifocal leukoencephalopathy (PML), which the JC virus causes. We now are able to risk stratify MS patients into high- and low-risk groups for developing PML on the basis of the presence or absence of antibodies to the JC virus, history of prior use of immunosuppressants, and duration of therapy with natalizumab. Fingolimod appears to be associated with a risk of asystole and sudden death. It may also increase the risk of serious herpes infections and paradoxical activation of MS. More information is needed about these serious side effects from fingolimod to allow us to use it safely in patients.