Inflammation occurs rapidly in response to acute brain insults such as stroke, haemorrhage or trauma, and can be sustained for long periods of time for example in Alzheimer’s, Parkinson’s and multiple sclerosis. Experimental evidence indicates that inflammation plays a major role in neurodegeneration in these conditions and that the cytokine interleukin-1 (IL-1) is a pivotal mediator. IL-1 is expressed rapidly after neuronal injury, predominantly by microglia and elevated levels of endogenous or exogenous IL-1 markedly exacerbates injury. The naturally occurring IL-1 receptor antagonist (IL-1RA) markedly inhibits ischaemic, excitotoxic and traumatic brain injury in rodents, and has shown promise in a Phase II clinical trial in stroke patients. The mechanisms of IL-1 expression, release and action in neurodegeneration are not fully elucidated and appear multiple. Systemic IL-1 markedly enhances ischaemic brain injury via release of neutrophils into circulation, neutrophil adhesion to injured cerebrovasculature and CNS invasion. Activation of matrix metalloproteinase 9 (MMP-9) occurs rapidly in neutrophils which have entered the CNS leading to cleavage of extracellular matrix and neuronal injury. IL-1 expressed within the CNS (primarily by microglia) acts on astrocytes to release neurotoxins including MMP-9, thus killing neurones indirectly via release of plasminogen. IL-1 can also influence neurones directly, for example to release IL-1β, via non-classical signalling pathways. IL-1RA, delivered peripherally can enter the CNS in animals and patients and has no adverse effects in stroke or sub-arachnoid haemorrhage patients.