Multiple sclerosis (MS) is a chronic inflammatory disease of central nervous system (CNS) resulting in various disabilities including weakness and imbalance, visual abnormalities, changes in cognition, as well as bladder and sexual dysfunction. The majority of patients begin with a relapsing-remitting course of the disease until eventually there is a progressive decline in disability. With FDA-approved disease modifying therapy now given to the majority of MS patients early in the course of the disease, the advent of MRI imaging, as well as advances in immunology and genetics, the study of MS has entered into an exciting era. Natural history studies of untreated patients have provided a guide for disease prognosis based on the clinical features of the disease but have limited utility in this new era of MS. Major questions are unanswered, including how does treatment affect the long-term clinical course of the disease and are there major subcategories of the disease with different implications for treatment and outcome. Advances in our ability to clinically measure and monitor the disease through MRI imaging technology, immunology, and genetic analysis provide the opportunity to address these critical questions.