Relapses are a defining feature of multiple sclerosis (MS), serving as the basis for categorizing the different phases of the disease, and providing a means of measuring treatment success, following disease activity, and defining prognostic features. While the dissociation between relapses and disease progression indicates the boundaries of relapse history in determining disease course over time, it also highlights the importance of relapses to overall disease evolution. A broad understanding of relapse definition and dynamics is important to promote accurate diagnosis, patient management, and treatment decisions. In an attempt to describe the underlying etiology and clinical impact of relapses in MS, this review will examine relapse findings from natural history studies, the utility of relapse as a predictor of disease course, the factors that may contribute to relapse, and data on relapse resolution. The relationship of clinical relapses to MRI disease activity and to the onset of progressive disease will also be addressed.