Multiple sclerosis (MS) is the leading nontraumatic cause of neurologic disability in young adults. Interferon-beta, approved for use in 1993, was the first treatment to modify the course and prognosis of the disease and remains a mainstay of MS treatment. Numerous large-scale clinical trials in early, active patient populations have established the clinical efficacy of interferon-beta in reducing relapses and delaying disability progression. Although its mechanism of action remains incompletely understood, a reduction in active lesions seen on magnetic resonance imaging implies primary anti-inflammatory properties, a mechanism supported by basic immunologic research. Variation in individual patient responsiveness to interferon-beta may be due to disease variability or differential induction of interferon-stimulated genes. The magnitude of the therapeutic effect appears to be similar among products, but the optimal dose, route, and frequency of administration of the drug remain uncertain.