Leishmaniasis is a vector-borne Neglected Tropical Disease (NTD) transmitted by the sand fly and is a major public health problem worldwide. Infections caused by Leishmania clinically manifest as a wide range of diseases, such as cutaneous (CL), diffuse cutaneous (DCL), mucosal (MCL) and visceral leishmaniasis (VL). The host innate and adaptative immune responses play critical roles in the defense against leishmaniasis. However, Leishmania parasites also manipulate the host immune response for their survival and replication. In addition, other factors such as sand fly salivary proteins and microbiota also promote disease susceptibility and parasite spread by modulating local immune response. Thus, a complex interplay between parasite, sand fly and the host immunity governs disease severity and outcome. In this review, we discuss the host immune response during Leishmania infection and highlight the factors associated with resistance or susceptibility.