Multiple sclerosis (MS) arises in people who have a genetic susceptibility to environmental factors and events, which ultimately trigger the disease. It is thought that peripheral immune cells are mobilized and enter the CNS through the impaired blood–brain barrier in the subarachnoid space, as acute lesions show large numbers of macrophages and CD8+ T cells and, to a lesser extent, CD4+ T cells, B cells and plasma cells. Demyelination is mostly localized to focal lesions in early relapsing–remitting (RR) MS, whereas other areas of white matter appear normal. Over time, T-cell and B-cell infiltration becomes more diffuse and axonal injury more widespread, leading to self-perpetuating atrophy in both white and gray matter. With disease progression, inflammatory processes are predominantly driven by the action of CNS resident microglia cells. In addition, there is evidence that meningeal lymphoid-like structures can form and contribute to late-stage inflammation. In general, however, despite dynamic changes over time in MS pathology, lesions do not appear to differ significantly in the different classic forms of MS already identified. While all treatments approved for MS management target inflammatory components of RRMS, the B-cell-depleting antibody ocrelizumab is the first such treatment approved recently for primary progressive (PP) MS. However, recent pathological and imaging findings have prompted reconsideration of the clinical phenotypes of MS patients proposed by Lublin's 2013 classification, including clinical and MRI signs of activity, and new imaging biomarkers of remyelination are now being investigated for new strategies of MS management.