Leishmania species infect approximately 2 million people each year and 350 million people live in areas where they are at risk for infection. This vector-transmitted disease causes significant morbidity and mortality in tropical and subtropical regions of the world and its impact on global health has increased substantially in light of the rise of HIV infection. More recently, military incursions into Leishmania-endemic regions have highlighted the importance of this parasitic infection. Leishmania parasites are transmitted by the bites of infected female sand flies of the genre Lutzomyia in the Western Hemisphere and Phlebotomus in Asia, Africa and southern Europe. Infections present as self-limiting cutaneous lesions, mucocutaneous infection, or disseminated visceral disease responsible for the vast majority of fatalities. While extensive work has been done to characterize these infections, an appropriate treatment or vaccine is still not available. In this light, there is a pressing need to continue immunological research on this important parasite. Leishmania is the prototypical model of the T helper 1/T helper 2 (Th1/Th2) dichotomy of the immune response. These two extremes in response to infection have been best characterized in mouse models and lead to the control and elimination of pathology in case of Th1 and in uncontrolled infection and tissue damage in the case of Th2. Because Leishmania has been shown to utilize complement receptor 3 (CR3) to enter host cells and CR3 has been reported to downregulate Th1 responses, the role of CR3 in in vivo infection was characterized in Chapter 2. Our studies reveal that CR3 deficiency leads to heightened, albeit not complete, resistance to Leishmania major on a susceptible Balb/c background. A growing body of evidence indicates that Leishmania and other intracellular pathogens do not passively infect their hosts. Rather, many pathogens manipulate their hosts in such a way as to make them more hospitable to infection. In Chapter 3, we examine how CR3 affects host cell responses to L. major and how infection may act to modulate macrophage cell signaling events that would lead to appropriate activation and parasite killing. This includes looking at the activation of mitogen activated protein kinases (MAPK), the translocation of transcription factors into cell nuclei, and the production of effector molecules like nitric oxide (NO). Chapter 4 presents our investigation of CR3 and Leishmania infection in resistant C57BL/6 mice. This chapter will outline our results examining parasite phagocytosis, production of Th1-driving interleukin-12 (IL-12), and mitogen-activated protein kinases (MAPK) and interferon-gamma (IFN-γ)-mediated cell signaling. Chapter 5 draws on our research and the extensive body of literature that dissects Leishmania-host immune interactions to attempt to build a framework wherein we can begin to unravel the often contradictory mechanisms involved in Leishmania infection. In addition, we will consider future directions for research in this area.