Anti-CD20 monoclonal antibodies effectively deplete peripheral inflammatory B-cells and CD20-expressing T-cells in multiple sclerosis (MS). Approval of these agents has therefore led to successful prevention of relapses from new local inflammatory lesion formation, but questions remain over whether central nervous system (CNS) B-cells can be targeted. Amit Bar-Or, MD, FRCPC, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, discusses the current approaches under investigation that may extend the use of B-cell-targeted therapies. A new area of interest is Bruton’s tyrosine kinase (BTK) inhibitors. These small molecules can target infiltrating B-cells and myeloid cells in the periphery, but can also access the CNS to target resident B-cells and microglia. Therefore, BTK inhibitors may target progressive disease as well as relapses. This interview took place during the ACTRIMS Forum 2021.