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Histamine is a biogenic amine with a broad spectrum of activities in various physiological and pathological conditions. Beside its well characterized effects in allergic responses and acute inflammation, histamine modulates the cytokine network, influencing T helper 1 and T helper 2 balance and antibody isotype. In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), there are several steps in the autoimmune attack against myelin of the central nervous system where histamine has been shown to play important roles. In this review, we summarize the evidences supporting the hypothesis of a significant contribution for histamine in autoimmune demyelinating diseases of the central nervous system. A deeper appreciation of the mechanisms by which histamine regulates the development of EAE and MS might have relevance in the therapy of these diseases.