Inflammatory diseases of the central nervous system (CNS) mainly occur during early adulthood and multiple sclerosis (MS) represents the overwhelming majority of these disorders. Nevertheless, MS only rarely begins after 50 years and a diagnosis of late-onset MS should only be done when clinical as well as radiological and biological findings are typical of MS since the probability of misdiagnosis is higher in elderly patients. Indeed, in patients aged over 50 years, along with a relative decrease of MS incidence, other inflammatory diseases of the CNS but also differential diagnoses including neoplastic as well as infectious disorders should be thoroughly searched to avoid diagnostic mistakes and the prescription of inadequate and potentially harmful immunomodulatory/immunosuppressive therapies. Moreover, aging is associated with diverse immune changes also known as immunosenescence resulting in, notably, higher risk of comorbidities (including vascular diseases) and infections which need to be considered when planning medical treatments of elderly patients with inflammatory diseases of the CNS. Herein, therapeutic and diagnostic challenges faced by neurologists are reviewed to ease patient management.