The rational development of disease-modifying therapies for multiple sclerosis (MS) requires a detailed knowledge of disease pathogenesis, but this remains incomplete. Dynamic computer-assisted modeling of MS is currently hindered by uncertainties about the connectivity, compartmentalization, and dynamic sequencing of the components of the disease process. The present work presents a simple but versatile model of the mammalian immune system, incorporating both innate and adaptive immunity and innate and adaptive tolerance. The model is applied to MS and its animal model, experimental autoimmune encephalomyelitis (EAE), to interrogate the concept of initiation of MS lesions through activation of the peripheral innate immune system, triggering auto-reactive T cells against myelin antigens in the central nervous system (CNS). The model also addresses the modulation of pro-inflammatory neurotoxic responses by the generation of regulatory T cells (adaptive tolerance) and clarifies the role of innate tolerance, a part of the immune system that has been little explored in MS to date. Some ramifications of the model are mentioned, including its relevance to existing disease-modifying therapies and the need to look more closely at the innate immune system for future therapeutic targets. Drug Dev Res 72:674–688, 2011. © 2011 Wiley Periodicals, Inc.