Abstract Multiple sclerosis (MS) is a lifelong neurologic disease leading to moderate or severe disability in the majority of affected patients. Studies of the natural history of MS suggest that 90% of patients with relapsing–remitting MS eventually develop secondary progressive (SP) disease. Magnetic resonance imaging (MRI) studies have consistently shown a high frequency of new T2 lesions and new gadolinium enhancing lesions even in the absence of clinical relapse. Lesion burden on T2 MRI increases by 5% to 10% per year and both axonal transection and cerebral atrophy are present at the earliest stages of RR MS. A wealth of evidence suggests that MS is a disease process that is continuously active, and that irreversible damage occurs early in the disease. Despite knowledge of the natural history and the availability of treatments that reduce relapse rates, decrease the accumulation of disability, and decrease surrogate measures of disease activity, only 60% of eligible patients have been treated with immunomodulating agents. This paper reviews the available evidence suggesting that immunomodulatory therapy modifies the natural history of MS and presents an argument for early intervention in the treatment of MS.