The ability to rapidly and efficiently recognize and eliminate pathogens while sparing normal self tissue is a hallmark of the mammalian immune system. When it fails, however, autoimmune disease results. The genetic and environmental factors that control the process of making such distinctions, not to mention the specific targeted tissues, are extraordinarily complex in the human population; only now are we characterizing the candidate genes responsible for these responses to pathogens. The examination of specific traits in murine models of disease has led to the identification of many of the candidate genes for human disease. The study of mouse mutations (both induced and spontaneous) has also greatly advanced our understanding of the immune responses and autoimmune disease. Here, we describe the use of classical mouse genetics to identify one gene centrally involved in the control of immune responses. Furthermore, although mutations in the orthologous human gene result in a virtually identical phenotype to that seen in the mouse, it is unlikely that studying the human disease populations alone would have successfully identified this gene. Thus, despite the complete sequencing of the human and mouse genomes, the examination of murine mutations remains a powerful and unbiased tool to connect genotype and phenotype.