Understanding the immune response in the central nervous system (CNS) is crucial for the development of new therapeutic concepts in chronic neuroinflammation, which differs considerably from other autoimmune diseases. Special immunologic properties of inflammatory processes in the CNS, which is often referred to as an immune privileged site, imply distinct features of CNS autoimmune disease in terms of disease initiation, perpetuation, and therapeutic accessibility. Furthermore, the CNS is a stress-sensitive organ with a low capacity for self-renewal and is highly prone to bystander damage caused by CNS inflammation. This leads to neuronal degeneration that contributes considerably to the phenotype of the disease. In this chapter, we discuss recent findings emphasizing the predominant role of the adaptive immune system in the pathogenesis of chronic neuroinflammation, that is, multiple sclerosis (MS) in patients and experimental autoimmune encephalomyelitis (EAE) in rodents. In addition, we report on efforts to translate these findings into clinical practice with the aim of developing selective treatment regimens.