The Expanded Disability Status Scale (EDSS) represents the most widely accepted measure of disease progression in multiple sclerosis (MS), and is used in many natural history studies. This chapter discusses natural history of relapsing onset MS, primary progressive MS, changes in natural history and impact on clinical trial design, traditional prognostic factors, and other factors which may influence prognosis such as race, comorbid diseases, and health behaviors. Pharmacoepidemiological studies using real world data derived from clinical practice represent a cost-effective means of evaluating the long-term effectiveness of immunomodulatory drug treatments for MS. Along with evidence from the basic sciences, epidemiological studies can provide insights into potentially novel treatments, as well as the rationale and hypotheses for testing these treatments in clinical trials. For example, vitamin D and estrogen are being evaluated in clinical trials based partly on epidemiological observations. Heterogeneity remains the hallmark of MS.