Multiple sclerosis is a chronic inflammatory disease of the central nervous system with profound heterogeneity in clinical course, neuroradiological presentation and response to therapy. The pathological analysis of 235 actively demyelinating lesions coming from three centers revealed different structural and immunological features suggesting that different pathogenetic mechanisms are involved in lesion formation. On the basis of the presence or absence of immunoglobulin and complement deposition, myelin protein loss and the patterns of oligodendrocyte degeneration beside a T cell- and macrophage-dominated immune response, four distinct patterns of demyelination have been identified. In this short review, possible paraclinical markers for tissue destruction on the basis of the main features of myelin destruction are discussed. Furthermore, the importance of early axonal damage in multiple sclerosis is highlighted.