The genetic basis for susceptibility to experimental autoimmune encephalomyelitis (EAE) has been the subject of intense study for several decades. In spite of this long history, however, the effort has only yielded small hints and contradictory leads to which genes influence susceptibility to this autoimmune disease. EAE is a prototypical model of autoimmunity that differs from other autoimmune diseases since it is relatively easily induced and quickly diagnosed in a wide range of strains and species. It also typically shows what looks, at first glance, to be a simple autosomal dominant inheritance pattern, making it appear to be an ideal disease to be solved genetically. In reality, however, the underlying genetics of EAE are much more complex than they appear on the surface, and the disease itself has a complex pathology that is only just beginning to be understood. With the advent in the last few years of transgene and knockout technologies and progress on the mapping and sequencing of genomes, strides are finally being made that promise to make an understanding of the genetics of EAE susceptibility a realizable goal. EAE is well established as a model for the human disease multiple sclerosis (MS), with resemblance in both its clinical and pathological features. Unlike MS, however, which is a spontaneous disease of unknown etiology, EAE is induced by driving the immune system to attack the brain and spinal cord through an immunization with any of several well-described central nervous system (CNS) myelin proteins. The disease that ensues begins with an inflammatory reaction in the white matter of the brain and spinal cord, causing both edema and myelin damage. As the inflammation progresses, damage to the myelin, which normally forms an insulating sheath around axons, leads to a disruption in the transmission of nerve signals along the spinal cord. This disruption typically manifests outwardly as paralysis in the tail and limbs.