While not all multiple sclerosis (MS) relapses require treatment, relapses that are bothersome or that impair function should prompt consideration of timely treatment to restore function and minimize disability. Patients with suspected MS relapses should be evaluated to confirm the diagnosis, exclude other causes of neurological dysfunction, and identify potential triggers for relapse or pseudo-relapse, such as urinary tract infections, fever, or metabolic derangements. The diagnosis of an MS relapse is clinical, but MRI may be useful for confirmation and to evaluate for multifocal disease activity. High-dose oral or intravenous glucocorticoids, with or without an oral taper, are first-line therapy for MS relapses. Adrenocorticotropic hormone (ACTH) provides an alternative to glucocorticoid treatment but is currently much more expensive and does not have proven superiority. If the acute neurological deficits remain severe after steroid treatment, and particularly if there is persistent abnormal contrast-enhancement of the symptomatic lesion on repeat MRI, plasma exchange (PLEX) should be considered as an acute rescue therapy for relapse. In exceptional cases, particularly fulminant or tumefactive disease that fails to improve following treatment with steroids and PLEX, cytoxic agents such as cyclophosphamide or B cell-depleting regimens such as rituximab may be considered, although risk must be carefully weighed and the kinetics of such regimens indicate that they probably serve more to accelerate remission of disease activity than as an immediate relapse remedy. A single dose of natalizumab given as acute therapy for MS relapse was shown not to improve clinical outcomes in a randomized controlled trial. Attention to symptom management and promotion of neurorehabilitation are important aspects of MS relapse care. Neuroprotective and neuroreparative therapies remain under investigation, but are likely to become important complementary elements of relapse therapy in the future. Relapses serve as important indicators of MS disease activity. In the context of the emerging treatment paradigm of targeting freedom from evidence of MS disease activity, relapses should prompt consideration of transitioning to a disease-modifying treatment that may offer better efficacy.