OBJECTIVE Neuroinflammation appears to be an important pathogenic process in amyotrophic lateral sclerosis (ALS). Dysfunction of central immune pathways, including activation of microglia and astrocytes, and peripherally derived immune cells, initiate noncell autonomous inflammatory mechanisms leading to degeneration. Cell autonomous pathways linked to ALS genetic mutations have been recently identified as contributing mechanism for neurodegeneration. The current review provides insights into the pathogenic importance of central and peripheral inflammatory processes in ALS pathogenesis and appraises their potential as therapeutic targets. RESULTS ALS is a multistep process mediated by a complex interaction of genetic, epigenetic, and environmental factors. Noncell autonomous inflammatory pathways contribute to neurodegeneration in ALS. Activation of microglia and astrocytes, along with central nervous system infiltration of peripherally derived pro-inflammatory innate (NK-cells/monocytes) and adaptive (cell-mediated/humoral) immune cells, are characteristic of ALS. Dysfunction of regulatory T-cells, elevation of pro-inflammatory cytokines and dysbiosis of gut microbiome towards a pro-inflammatory phenotype, have been reported as pathogenic mechanisms in ALS. CONCLUSIONS Dysregulation of adaptive and innate immunity is pathogenic in ALS, being associated with greater disease burden, more rapid disease course and reduced survival. Strategies aimed at modulating the pro-inflammatory immune components could be of therapeutic utility.