The role of B cells in the pathophysiology of multiple sclerosis (MS) extends beyond antibody synthesis, also involving the modulation of T lymphocytes and myeloid cells. B-cell activation within the Central Nervous System is associated with the release of various antibodies, cytokines, and chemokines, measurable in biofluids, thereby serving as biomarkers of the immune processes responsible for MS. To this purpose, a biomarker-based characterization of the disease through the combination of well-established markers, e.g., immunoglobulin (Ig) G index, IgG oligoclonal bands, Ig free light chains, with new promising markers, namely chemokine (C-X-C motif) ligand 13, and B-cell activating factor/A proliferation-inducing ligand, might represent a significant improvement in the management of people with MS.