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Background: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS). During the of progression of EAE, microglia, the immunocompetent cells of the brain, become activated and accumulate around demyelinated lesions. Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression. In this study, we have used pharmacological inhibitors and stimulators of microglial/ macrophage activation to examine the temporal requirement for microglial activation in EAE progression and to determine whether such approaches might potentially be of therapeutic value. Results: Intervention using the tripeptide macrophage/microglia inhibitory factor MIF (TKP) and the tetrapeptide macrophage/microglial stimulator tuftsin (TKPR) attenuated EAE symptoms and revealed that the timing of macrophage/microglial activation is critical for the clinical outcome of EAE. We show that the disease progression can potentially be manipulated favorably at early stages by altering the timing of microglial activation, which in turn alters the systemic immune response to favor upregulation of T helper cell 2 genes that promote recovery from EAE. Conclusion: Preventative and therapeutic modulation of macrophage/microglial activity significantly alters the outcome of EAE at symptomatic stages. Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS. Background Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease with symptoms that include neurological impairment and motor deficits. MS results from immune attack on myelin, which leads to axonal and neuronal degeneration. A commonly used MS animal model is experimental autoimmune encephalomyelitis (EAE). EAE does not occur spontaneously, but does mimic some of the pathological and histological hallmarks of MS. During EAE, T cells recognizing components of myelin become activated, migrate to the CNS and cause autoimmune inflammation [1], which results in CNS infiltration of CD4+, CD8+ T cells and B cells. The inflammatory process includes secretion of proinflammatory T helper1 Published: 16 July 2007 BMC Immunology 2007, 8:10 doi:10.1186/1471-2172-8-10 Received: 26 October 2006 Accepted: 16 July 2007 This article is available from: http://www.biomedcentral.com/1471-2172/8/10 © 2007 Bhasin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.