B cells have been successfully targeted in autoimmune diseases. This includes neurodegenerative diseases occurring in the central nervous system (CNS) such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). This has shown that depletion of mature B cells benefits to MS and NMOSD patients. In this chapter, we will review the essential steps leading to approval of B-cell depletion therapies for these diseases. Notably, not all B-cell depletion therapies got successful in these diseases. However, the latter provided key bedside information that improved our knowledge of the diseases from the benchside.