The modern era of multiple sclerosis (MS) treatment began 25 years ago, with the approval of IFNβ and glatiramer acetate for the treatment of relapsing–remitting MS. Ten years later, the first monoclonal antibody, natalizumab, was approved, followed by a third important landmark with the introduction of oral medications, initially fingolimod and then teriflunomide, dimethyl fumarate and cladribine. Concomitantly, new monoclonal antibodies (alemtuzumab and ocrelizumab) have been developed and approved. The modern era of MS therapy reached primary progressive MS in 2018, with the approval of ocrelizumab. We have also learned the importance of starting treatment early and the importance of clinical and MRI monitoring to assess treatment response and safety. Treatment decisions should account for disease phenotype, prognostic factors, comorbidities, the desire for pregnancy and the patient’s preferences in terms of acceptable risk. The development of treatment for MS during the past 25 years is a fantastic success of translational medicine.