Natural transmission of Trypanosoma cruzi to human is established when feces of hematophagous triatomines contaminated with insect-derived from metacyclic trypomastigotes get in contact with the skin, conjunctiva or even oral route. Article is aimed at updating the knowledge about the early interaction between insect-derived metacyclic trypomastigotes at the port of entry and the host. There are few works in the literature describing this first contact between host and natural insect-derived metacyclic trypomastigote. Although it is currently accepted that T. cruzi parasites can penetrate through the lesion left by the insect´s bite, pioneer data do not support this hypothesis as the main via; however, once in the dermis metacyclic trypomastigotes can spread rapidly and likely escape from inoculation site through endothelial cells and disseminate to the body via the bloodstream. A moderate inflammatory reaction took place in the skin at the port of entry within hours, the cytokines induces recruit of neutrophils predominantly, probably because triatomine feces microbiota is present in the inoculum that in some way, its presence modify the progress of the infection.