Even prior to the introduction of criteria defining the radiologically isolated syndrome (RIS), longitudinal clinical data from individuals with incidentally identified T2 lesions suggestive of multiple sclerosis (MS) were described. Healthy individuals who do not exhibit signs of neurological dysfunction may have a brain MRI performed for a reason other than suspicion of MS that reveals unexpected anomalies highly suggestive of demyelinating plaques given their size, location, and morphology. These healthy subjects lack a history or symptomatology suggestive of MS and fulfill formal criteria for RIS, a recently described MS subtype that shares the phenotype of at-risk individuals for future demyelinating events. A formal description of RIS was first introduced in 2009 by Okuda et al., and defines a cohort of individuals who are at risk for future demyelinating events. European or North American observational studies have found that up to 30–45% of patients presenting with RIS will present with neurological symptoms, either acute or progressive. The median time to clinical conversion differs between studies. It was 2.3 years for a series of French patients and 5.4 years for an American cohort. Most patients who developed clinical symptoms had prior radiological progression. The presence of asymptomatic lesions in the cervical cord indicated an increased risk of progression, either to relapsing or to progressive MS. The consortium studying the epidemiology of RIS worldwide (RISC) presented their first retrospective cohort last year. Data were available for 451 RIS subjects (F: 354 [78.5%]). The mean age at RIS diagnosis was 37.2 years with a mean clinical follow-up time of 4.4 years. The observed 5-year conversion rate to the first clinical event was 34%. Of the converters within this time period, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age, sex (male), and lesions within the cervical or thoracic spinal cord were identified as significant predictors for the development of a first clinical event. Cognitive impairment is observed in RIS patients, and two studies demonstrated a significant proportion of patients with cognitive decline compared with healthy controls. Despite progress into the characterization of RIS subjects and into our understanding of risk factors for initial symptom development, the natural course of such cases and risk-profiles for a seminal neurological event, from prospectively acquired data, remain unclear. A prospective study is mandatory to increase our knowledge about these asymptomatic patients and individual therapeutic initiatives cannot be undertaken until a prospective clinical study demonstrates the benefit of introducing a disease modifying treatment for this very early stage of a chronic demyelinating disease.