Anti-CD20 monoclonal antibodies are highly-effective B-cell-depleting therapies in multiple sclerosis (MS). These treatments have expanded the arsenal of highly effective disease-modifying therapies, and have changed the landscape in understanding the pathophysiology of MS and the natural course of the disease. Nevertheless, these treatments come at the cost of immunosuppression and risk of serious infections, diminished vaccination response and treatment-related secondary hypogammaglobulinemia. However, the COVID pandemic has given way to a possibility of readapting these therapies, with most notably extended dosing intervals. While these new strategies show efficacy in maintaining inflammatory MS disease control, and although it is tempting to speculate that tailoring CD20 therapies will reduce the negative outcomes of long-term immunosuppression, it is unknown whether they provide meaningful benefit in reducing the risk of treatment-related secondary hypogammaglobulinemia and serious infections. This review highlights the available anti-CD20 therapies that are available for treating MS patients, and sheds light on encouraging data, which propose that tailoring anti-CD20 monoclonal antibodies is the next step in rethinking the current treatment strategy.