Neuropathological studies of early multiple sclerosis (MS) tissue have shaped prevailing views of the pathogenesis of the disease. The hallmark of the acute MS lesion, inflammatory demyelination, has been largely accepted as evidence of a macrophage-mediated attack on normal myelin, driven by perivascular and parenchymal autoreactive CD4+ Th1 cells primed in the periphery by an unknown self or foreign antigen(s). Predicated largely upon comparisons with experimental allergic encephalomyelitis, this paradigm has, in recent years, been recognized as a simplification of the events that constitute and perhaps presage lesion formation in the human disease; and the importance of the innate immune cells of the central nervous system, humoral factors, cytotoxic CD8+ T-cells and regulatory T-cells has been emphasized. An influential series of publications by one group, based on histopathological examination of actively demyelinating lesions in selected autopsy and biopsy MS tissue, defined four early lesion subtypes. In a given individual, these subtypes were reported to be mutually exclusive, suggesting that disparate pathogenetic pathways separate patients with clinically indistinguishable syndromes. This schema, which has considerable therapeutic implications, has not been independently verified and has recently been questioned by the finding of a uniform pre-phagocytic pathology and overlap of lesion subtypes in individual patients with typical relapsing and remitting disease. The latter findings would suggest that the heterogeneous features observed in active MS lesions sampled at different time-points are a reflection of the evolution of a single pathophysiological process, perhaps modified in part by genetic factors in individual cases.