Leishmania major infection of inbred mice leads to a major dichotomous response--death or survival--that depends on the strain of mice. This finding has motivated efforts to locate genetic determinants of disease susceptibility. Genotyping studies have confirmed a complex multilocus trait, but studies directed at the biology of the response suggest identifiable components of susceptibility that may direct the genetic investigations. A confluence of parasite variables--residence in macrophages class II-dependent immunity, and avoidance of early IL-12 induction--with host factors--a prominent helper T-cell precursor frequency to a dominant parasite epitope and a bias in IL-4 gene activation--conspires to drive an aberrant immune response in animals that suffer fatal disease. These insights may lead to an understanding of factors that focus responses on dominant antigens and that mold the naive T-cell repertoire. Collectively, such factors might contribute to the pathogenesis of other infectious and autoimmune diseases.