Multiple sclerosis (MS) is the most frequent chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) affecting people from young adulthood. While existing disease-modifying treatments effectively control peripheral immune responses and mitigate the relapse-associated inflammatory activity, they demonstrate limited efficacy in halting disease progression that occurs independently of relapses. Preventing or treating clinical progression is a major unmet need in MS. Growing evidence supports the role of compartmentalized inflammation within the leptomeninges and within the parenchyma, as occurring in chronic active lesions, in clinical progression. Chronic active lesions are destructive and do not remyelinate, and they are the site of smoldering inflammatory demyelination and of ongoing axonal injury. The recent possibility to image in vivo chronic active lesions in the brain (as paramagnetic rim lesions using susceptibility-based MRI) led to the recent discovery of their important role in driving early disability accrual and potentially progression. Dissecting the molecular mechanisms underlying chronic inflammation in the CNS and fostering its resolution are key research goals of the Translational Neuropathology Unit.