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BACKGROUND Neuropathology played a major role in deciphering disease mechanisms in multiple sclerosis. METHODS Retrospective review of neuropathological studies, published during the last two decades. RESULTS The importance of neuropathology is generally seen in its contribution to the diagnosis of diseases of the nervous system, in particular in neuro-oncology. However, when it also includes in its analysis the global three-dimensional extension of brain damage and the temporal sequence of lesion evolution and relates this to molecular changes in the lesions, it offers the potential to decipher disease pathogenesis and to contribute to the development of effective and causative treatments. In multiple sclerosis research neuropathology was essential to discriminate the disease from other inflammatory autoimmune or demyelinating diseases, such as neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD). It defined the hallmark of chronic progressive disease in MS patients as slowly expanding tissue damage around lesions and in the normal appearing white and grey matter. It showed that these changes occur in the course of a tissue resident immune response within the central nervous system, involving tissue resident effector memory cells and plasma cells. Molecular studies in neuropathologically defined micro-dissected MS lesions identified a cascade of oxidative injury, mitochondrial damage and subsequent virtual hypoxia as a major pathway of tissue injury in MS. CONCLUSIONS The results of these studies were highly relevant for the identification of potential therapeutic targets in MS patients and the design of pivotal clinical trials.