The host’s ability to eradicate or control infection caused by intracellular pathogens depends on early interactions between these microorganisms and host cells. These events are related to the organism’s nature and stage of development and host immune status. Pathogens are recognized by host cells, which respond to infection by either mounting an efficient response or becoming a replication niche. Early interactions between the protozoan Leishmania parasite and host cell receptors activate different signaling pathways that can result in microbe elimination or, alternatively, infection establishment and the migration of Leishmania infected cells to other host tissues. This chapter focuses on Leishmania-macrophage interaction via phagocytosis, which involves a range of parasite ligands characteristic of Leishmania species and parasite stage of development and diverse host cell receptors. We also discuss alternative Leishmania entry by cell invasion and review how Leishmania spp. survive and replicate within the phagocytic compartment they induce.