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At the sites of motor neuron injury, accumulation of activated microglia, the primary immune cells of the central nervous system, is commonly observed in both human <jats:italic>post mortem<\/jats:italic> studies and animal models of MND. Microglial activation has been found to correlate with many clinical features and importantly, the speed of disease progression in humans. Both anti\u2010inflammatory and pro\u2010inflammatory microglial responses have been shown to influence disease progression in humans and models of MND. As such, microglia could both contribute to and protect against inflammatory mechanisms of pathogenesis in MND. While murine models have characterized the microglial response to MND, these studies have painted a complex and often contradictory picture, indicating a need for further characterization in humans. This review examines the potential role microglia play in MND in human and animal studies. 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