A clinically isolated syndrome (CIS) is a term which describes the first clinical onset of a potential multiple sclerosis (MS). It ought to be defined as an MS stage rather than a separate disease entity; however, with respect to the diagnostic work-up, differential diagnoses to be considered, prognostic factors for the development of a clinically confirmed MS and initiation of an immunomodulatory therapy, there are some important considerations supported by recent studies. These considerations as well as the current guidelines are critically discussed in this review article. Additionally, recommendations are given regarding the management of radiologically isolated syndrome (RIS) an imaging-based diagnosis of a potential preclinical stage of MS.