Multiple sclerosis (MS) is the most common cause of nontraumatic severe neurological disability in young adults. If left untreated, most individuals with MS will accumulate significant physical and/or cognitive disability as the consequence of demyelination and axonal injury. Treatment has focused on disease-modifying therapies (DMTs) and questions remain about timing and indications for their use. Natalizumab is a humanized monoclonal antibody directed against alpha4-integrin that prevents migration of leukocytes into the brain parenchyma. The clinical and radiological efficacy of natalizumab has been shown in several randomized trials; however, adverse events associated with natalizumab have limited its use as a first-line agent. In this review we compare current recommendations for the use of first-line DMTs, adverse events associated with MS therapies, and differences between the practices in North American and the European Union.