LEW and BN rats, that behave in opposite ways for their susceptibility to various immune-mediated diseases, provide a powerful model to investigate the molecular and genetic bases of immune system physiology and dysregulation. Using this model, we addressed the question of the genetic control of central nervous system autoimmunity, of xenobiotic-induced allergic diseases, and of T cell subsets that differ by their cytokine profiles. By linkage analysis and genetic dissection, using a panel of congenic rats, we identified a 120 Kb region on chromosome 9 that controls all these phenotypes, indicating that this region contains a gene or set of genes that plays an important role in the immune system homeostasis and susceptibility to immune mediated diseases. In this review, we will describe these rat genomics studies and will discuss the cellular and genetic factors that may be involved in the differences between these rat strains.