Leishmaniasis is a parasitic, widespread, and neglected disease that affects more than 90 countries in the world. More than 20 <i>Leishmania</i> species cause different forms of leishmaniasis that range in severity from cutaneous lesions to systemic infection. The diversity of leishmaniasis forms is due to the species of parasite, vector, environmental and social factors, genetic background, nutritional status, as well as immunocompetence of the host. Here, we discuss the role of the immune system, its molecules, and responses in the establishment, development, and outcome of Leishmaniasis, focusing on innate immune cells and <i>Leishmania major</i> interactions.