In this chapter, we will examine the mechanisms by which Leishmania parasites interact with host cells. We will try to develop the hypothesis that the success or failure of Leishmania infections can be traced to the initial mechanism(s) of parasite entry into mononuclear phagocytes. We will try to make the following points about the activation and modulation of innate immunity by Leishmania: First, promastigotes enter macrophages by a quiescent mecha­ nism that fails to induce innate immune responses, and this may result in a delayed induction of an adaptive immune response. This delay in the development of adaptive immunity may pro­ vide the parasite with time to replicate within macrophages. Second, parasite replication dis­ rupts macrophage responsiveness to the immune signals that are eventually generated. Third, the mechanism of amastigote entry into macrophages may also be the harbinger for successful parasitism. Amastigotes coat themselves in host IgG which ligates macrophage FcyR, resulting in the hyperproduction of IL-10 from infected macrophages. This IL-10 can prevent macroph­ age responses to IFN-γ allowing the parasites to survive even in the immunologically intact host.