Autoimmune inflammation in the central nervous system (CNS) plays a significant role in multiple sclerosis (MS), suggesting that regional lymph nodes are involved in pathogenesis of the disease. The brain has two fluids that drain to lymph nodes: cerebrospinal fluid (CSF) and interstitial fluid (ISF). CSF drains via nasal lymphatics and carries antigens, antigen-presenting cells (APCs), and inflammatory cells to cervical lymph nodes (CLNs). There are no conventional lymphatics in the parenchyma of the CNS; instead, ISF and soluble antigens drain to lymph nodes along narrow basement membranes in the walls of capillaries and arteries. This route is too narrow to allow the migration of APCs. Lymphatic drainage of CSF and ISF appears to confer tolerance to CNS proteins upon the CLNs. Such tolerance may be eclipsed when systemic exposure to brain antigens primes lymphocytes against CNS antigens, as occurs in experimental autoimmune encephalomyelitis. Similar mechanisms may apply to the pathogenesis of MS.