Incidental brain magnetic resonance imaging (MRI) findings are the result of an increasing usage of MRI in the diagnostic work-up of patients. An adequate assessment of patients in which brain lesions typical for multiple sclerosis (MS) are determined but who have been asymptomatic so far is problematic, especially when Barkhof-Tintoré criteria for spatial dissemination are fulfilled and no other differential diagnosis can be confirmed. This entity, the so-called radiologically isolated syndrome, constitutes a major diagnostic and therapeutic challenge. Two recent studies revealed that a subgroup of patients with radiologically isolated syndrome are at high risk for near-term development of MR-based progression and occurrence of the first clinical event. Hence, the radiologically isolated syndrome has to be classified as a possible preliminary phase of the clinical manifestation of MS in a subgroup of patients and entails in-depth therapeutic considerations. This article covers the current literature for this syndrome and, in the absence of official guidelines, provides a pragmatic diagnostic and therapeutic approach for patient management.