Eighty-five percent of patients with multiple sclerosis (MS) initially present with a single demyelinating event, referred to as a clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord. Following the onset of CIS, 38 to 68% of patients develop clinically definite MS (CDMS). Clinically silent brain lesions are seen on MRI in 50 to 80% of patients with CIS at first clinical presentation and 56 to 88% of CIS patients with abnormal MRI are at high risk of conversion to CDMS. Axonal damage, that is considered to underlie the development of persistent disability in MS, occurs in the CIS stage. Treatment with disease-modifying therapies (DMTs), that might prevent axonal damage and result in slowing the progression of disability, should be initiated early during the disease course. Clinical trials demonstrated that early treatment of CIS patients with the standard dose of interferon beta (IFNbeta) significantly reduced the risk of progression to CDMS by 44 to 50%. After 5 years of followup, the results of the IFNbeta treatment extension studies confirmed that the risk of conversion to CDMS was significantly reduced by 35 to 37% in patients receiving early treatment compared to that in those receiving delayed treatment. However, not every patient with CIS will progress to CDMS; the IFNbeta treatment is appropriately indicated for CIS patients who are diagnosed with MS by McDonald diagnostic criteria based on MRI findings of dissemination in space and time and are at high risk for conversion to CDMS. Development of more reliable prognostic markers will enable DMTs to be targeted for those who are most likely to benefit.