The diagnosis of multiple sclerosis has been increasingly standardized over the years and has evolved to incorporate new diagnostic modalities. The gold standard for diagnosing multiple sclerosis remains clinical, with dissemination of typical white matter symptoms and signs in time and space. The Schumacher criteria in 1965 attempted to standardize clinical criteria for diagnosing multiple sclerosis. The Poser criteria in 1983 added evoked potential and cerebrospinal parameters and the McDonald criteria in 2001 added MRI parameters. All criteria for diagnosing multiple sclerosis include the caveat that no alternative diagnosis better explains the clinical picture, making the differential diagnosis of multiple sclerosis critical. Recent availability of first generation immunotherapies for MS has increased pressure to make an early and accurate diagnosis of multiple sclerosis and to use the diagnostic work-up to try to prognosticate a future disease course.