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Randomized clinical trials and real\u2010world data demonstrate that modern disease\u2010modifying therapies substantially reduce relapse rates and acute inflammatory activity detected by magnetic resonance imaging (MRI). However, disability accumulation increasingly occurs independent of relapse activity, highlighting progression biology as the principal unmet need. Converging epidemiological and molecular evidence supports a pivotal role for Epstein\u2013Barr virus (EBV) infection in disease initiation, whereas later stages appear dominated by brain\u2010intrinsic mechanisms, including compartmentalized inflammation, microglial activation, failure of remyelination and accelerated biological ageing. Population\u2010based cohorts demonstrate that early high\u2010efficacy therapy improves long\u2010term outcomes, yet the risk of progression rises markedly after midlife despite effective relapse suppression. 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