Leishmania infection consists in two sequential events, the host cell colonization followed by the proliferation/dissemination of the parasite. In this review, we discuss the importance of two distinct sets of molecules, the secreted and/or surface and the nonsecreted antigens. The importance of the immune response against secreted and surface antigens is noted in the establishment of the infection and we dissect the contribution of the nonsecreted antigens in the immunopathology associated with leishmaniasis, showing the importance of these panantigens during the course of the infection. As a further example of proteins belonging to these two different groups, we include several laboratorial observations on Leishmania Sir2 and LicTXNPx as excreted/secreted proteins and LmS3arp and LimTXNPx as nonsecreted/panantigens. The role of these two groups of antigens in the immune response observed during the infection is discussed.