The development of antidrug antibodies (ADAs) is a major problem in several recombinant protein therapies used in the treatment of multiple sclerosis (MS). The etiology of ADAs is multifaceted. The predisposition for a breakdown of immune tolerance is probably genetically determined, and many factors may contribute to the immunogenicity, including structural properties, formation of aggregates, and presence of contaminants and impurities from the industrial manufacturing process. ADAs may have a neutralizing capacity and can reduce or abrogate the bioactivity and therapeutic efficacy of the drug and cause safety issues. Interferon (IFN)-β was the first drug approved for the treatment of MS, and—although it is generally recognized that neutralizing antibodies (NAbs) appear and potentially have a negative effect on therapeutic efficacy—the use of routine measurements of NAbs and the interpretation of the presence of NAbs has been debated at length. NAbs appear after 9–18 months of therapy in up to 40% of patients treated with IFNβ, and the frequency and titers of NAbs depend on the IFNβ preparation. Although all pivotal clinical trials of approved IFNβ products in MS exhibited a detrimental effect of NAbs after prolonged therapy, some subsequent studies did not observe clinical effects from NAbs, which led to the claim that NAbs did not matter. However, it is now largely agreed that persistently high titers of NAbs indicate an abrogation of the biological response and, hence, an absence of therapeutic efficacy, and this observation should lead to a change of therapy. Low and medium titers are ambiguous, and treatment decisions should be guided by determination of in vivo messenger RNA myxovirus resistance protein A induction after IFNβ administration and clinical disease activity. During treatment with glatiramer acetate, ADAs occur frequently but do not appear to adversely affect treatment efficacy or result in adverse events. ADAs occur in approximately 5% of patients treated with natalizumab within 6 months of therapy, and persistent NAbs are associated with a lack of efficacy and acute infusion-related reactions and should instigate a change of therapy. When using the anti-CD20 monoclonal antibodies ocrelizumab and ofatumumab in the treatment of MS, it is not necessary to test for NAbs as these occur very infrequently. Alemtuzumab is immunogenic, but routine measurements of ADAs are not recommended as the antibodies in the pivotal 2-year trials at the population level did not influence lymphocyte depletion or repopulation, efficacy, or safety. However, in some individuals, NAbs led to poor lymphocyte depletion.