A clinically isolated syndrome (CIS) is an isolated event that is suggestive of demyelination. CIS most commonly manifests as an optic neuritis (ON), transverse melitis, or a brainstem syndrome. Because most MS patients present initially with a CIS, most practicing neurologists deal with the challenges of managing these syndromes. This chapter integrates evidence-based knowledge of the natural history of CIS with published clinical trial data and proposes a practical guideline for the management of CIS. Clinical, imaging, and laboratory predictors of outcome in CIS are discussed. Various diagnostic criteria are proposed to confirm the dissemination of demyelination and to establish a diagnosis of MS. Head MRI at baseline is the most important predictive tool for evaluating the risk of CDMS after an episode of CIS. The pathology of early MS and CIS goes beyond the focal lesions, myelin, and the white matter. The neuromyelitis optica (NMO)-IgG autoantibody is a validated clinical biomarker that distinguishes NMO and related relapsing central nervous system (CNS) inflammatory demyelinating disorders from classic MS, which generally is less severe. The medical management of CIS involves the treatment of the acute attack and disease modifying therapies. The randomized CIS treatment trial results with an evidence-based approach are summarized.