The study of animal models for organ-specific autoimmune disease contributes to our understanding of human diseases such as multiple sclerosis and rheumatoid arthritis. Although experimental autoimmune diseases develop spontaneously in certain strains of mice, others need to be induced by administration of organ-specific autoantigen, often together with complete Freund’s adjuvant (CFA), containing heat-killed mycobacteria. In the two types of models, the role of endogenous interferon-γ (IFN-γ) has extensively been investigated by using neutralizing anti-IFN-γ antibodies and by employing mice genetically deficient in IFN-γ or its receptor. In these studies disease-promoting as well as disease-protective roles of endogenous IFN-γ have been described. Remarkably, in most models that rely on the use of CFA, there is abundant evidence for a protective role. Here, we review evidence that this role derives from an inhibitory effect of IFN-γ on myelopoiesis elicited by the killed mycobacteria. These findings explain the bimodal role of IFN-γ in different models of autoimmune disease and raise questions regarding the clinical relevance of these models.