Multiple sclerosis (MS) represents a spectrum of demyelination that depends on disease duration and clinical categorization. Most patients present with the relapsing-remitting form of the disease. The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS). Predicting which CIS patients are at high risk for MS is complicated by the disparity between clinical attacks and the extent of axon pathology. However, recent interferon-beta (IFN-beta) trials have demonstrated a delay in time to the second demyelinating event with early treatment, and early treatment could also slow the progression from RRMS to secondary-progressive MS (SPMS). Clinical findings in combination with brain MRI and CSF analysis can be used in CIS patients to evaluate their risk for clinically definite MS (CDMS). Application of the McDonald criteria also allows an earlier MS diagnosis by using new MRI lesions to define dissemination in time. Early immunomodulatory therapy for selected CIS patients may eventually prevent future axon pathology and progression of disability in this lifelong disease.