A clinically isolated syndrome is a first episode of central nervous system dysfunction due to inflammatory demyelination. Clinically isolated syndrome may be an isolated event, represent the first clinical manifestation of relapsing-remitting multiple sclerosis, or be secondary to an alternative process. Risk factors for conversion to clinically definite multiple sclerosis have been identified, and treatment of high-risk individuals may delay subsequent relapses. In this article, Dr. Elizabeth Hartman of the University of Illinois at Chicago summarizes the diagnosis, evaluation, and prognostic implications of clinically isolated syndromes. New MRI diagnostic criteria may allow earlier diagnosis of multiple sclerosis in select patients presenting with a clinically isolated syndrome.