Leishmania major is a protozoan parasite that is transmitted to the mammalian host by its sand fly vector when the fly probes in the host's skin for a blood meal and injects the parasite within its saliva. In mice experimentally infected with L. major, outgrowth of CD4 type 1 (Th1) cells leads to resolution of the infection, but outgrowth of type 2 (Th2) cells exacerbates disease. To design an effective vaccine against the parasite (and other pathogens that induce polarized Th1 and Th2 responses), we must determine the mechanism underlying this phenomenon so that we can design the vaccine to elicit the appropriate (i.e., protective) Th cell. Recent work indicates that Th bias is influenced by a number of signals delivered by antigen-presenting cells, including cytokines and co-stimulatory molecules. Moreover, recent work also suggests that sand fly saliva influences the immune response to L. major and Th polarization. Determining the mechanisms that lead to polarized Th responses should expand our knowledge regarding immunity to L. major, and should add to our understanding of immunoregulation in general.