Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, talks on the urgent need for therapies that tackle smoldering disease activity in multiple sclerosis (MS). Often referred to as silent progression or progression independent of relapse activity (PIRA), accumulation of disability outside of relapses is a major therapeutic challenge in MS. A wide range of therapies are now available that are able to tackle inflammatory activity in MS, but there is a lack of treatments for progressive disease. Prof. Giovannoni comments on several strategies under investigation based on a growing knowledge of the pathobiological mechanisms driving these processes. This interview took place at the ACTRIMS Forum 2022 in West Palm Beach, Florida.