Multiple sclerosis (MS) is a chronic progressive demyelinating autoimmune disorder of the central nervous system, that over time causes accumulating disability and worsening of a diverse range of symptoms. Currently, a number of disease-modifying treatments exist, capable of slowing the progression of MS. In addition, pharmacological treatments aimed at alleviating symptoms exist for some symptoms, whereas they have limited or no efficacy on others while causing frequent adverse effects. Therefore, nonpharmacological interventions with the potential to further slowdown disease progression or treat symptoms are highly warranted in MS. Over the past three decades, a paradigm change has taken place establishing exercise as a cornerstone of MS rehabilitation as opposed to previously where it was considered damaging. Today exercise studies have established exercise as an effective symptomatic treatment (i.e., tertiary prevention), but recent studies have evaluated the disease-modifying effects (i.e., secondary prevention) of exercise as well as the impact on the risk of developing MS (i.e., primary prevention) showing promising results here as well. Moreover, tailored training can help people with MS increase their muscle strength, cardiorespiratory fitness, balance, and coordination, while simultaneously reducing core symptoms such as fatigue and gait impairments. Furthermore, training may have positive effects on (preserving) cognition, but the evidence is not conclusive. This chapter describes the prevalence, incidence, prognosis, and pathophysiology of MS. In addition, characteristic symptoms associated with the disease are presented and treatment of many of these symptoms is discussed with a special focus on exercise and physical activity as interventions for people with MS. Finally, the chapter discusses the possible mechanisms, the available options, and the current challenges.