Vitamin D insufficiency has been shown to be associated with increased susceptibility to multiple sclerosis (MS), but until recently, it was unclear if vitamin D status also influences the prognosis of the disease. In experimental autoimmune encephalomyelitis, a mouse model of MS, the administration of vitamin D reduces the severity of the disease. Initial reports in MS of inverse associations between vitamin D levels and disability or relapse rate were encouraging, but the cross-sectional or retrospective study designs limited their interpretability. More recently, studies of pediatric-onset and adult MS have demonstrated that among those with established MS, those with lower vitamin D levels are at higher risk for subsequent relapse. These observational data provide strong support for randomized controlled trials of vitamin D supplementation in MS.