The article reviews the current landscape of treatments for multiple sclerosis (MS) using monoclonal antibodies (mAbs) targeting the CD20 receptor, including rituximab, ocrelizumab, ofatumumab, and ublituximab. These mAbs have significantly improved disease outcomes through their robust efficacy on clinical manifestations and MRI lesion activity, making them cornerstone treatments for MS. Ocrelizumab is the only therapy approved for primary progressive MS. The article discusses the role of B cells in MS pathogenesis, the molecular and pharmacological properties of anti-CD20 mAbs, and safety considerations such as immunogenicity, infusion-related reactions, hypogammaglobulinemia, and vaccine response. It also highlights ongoing clinical trials comparing the relative efficacy of these therapies and the potential benefits of alternative dosing schedules. The article emphasizes the need for CNS-penetrant therapies to address compartmentalized inflammation, which is thought to play a crucial role in disability progression.The article reviews the current landscape of treatments for multiple sclerosis (MS) using monoclonal antibodies (mAbs) targeting the CD20 receptor, including rituximab, ocrelizumab, ofatumumab, and ublituximab. These mAbs have significantly improved disease outcomes through their robust efficacy on clinical manifestations and MRI lesion activity, making them cornerstone treatments for MS. Ocrelizumab is the only therapy approved for primary progressive MS. The article discusses the role of B cells in MS pathogenesis, the molecular and pharmacological properties of anti-CD20 mAbs, and safety considerations such as immunogenicity, infusion-related reactions, hypogammaglobulinemia, and vaccine response. It also highlights ongoing clinical trials comparing the relative efficacy of these therapies and the potential benefits of alternative dosing schedules. The article emphasizes the need for CNS-penetrant therapies to address compartmentalized inflammation, which is thought to play a crucial role in disability progression.