Although programmed cell death protein-1 (PD-1) is expressed on CD4+ T, CD8+ T and B cells, the T cell expression of PD-1 and macrophages’ expression of its ligands- PD-L1 and PD-L2 increase during leishmaniasis. The PD-1/PD-L1 interaction induces T cell anergy, T cell apoptosis and exhaustion, diversion of T cells toward TH2 and T-reg cells and inhibition of M1 macrophage activities by suppression of nitric oxide (NO) and reactive oxygen species (ROS) production. These changes exacerbate Leishmania infection. As PD-L1-deficient, but not PD-L2-deficient, mice were protected against L. mexicana infection, differential roles have been proposed for PD-L1 and PD-L2 in mouse models of leishmaniasis. Blockade of PD-1/PD-L1 interaction in various in vitro and Leishmania-infected mouse, hamster and dog models enhanced IFN-γ and NO production, reduced IL-10 and TGF-β generation, promoted T cell proliferation and decreased parasite burden. Blockage of PD-1/PD-L1 axis can be considered as a potential therapeutic strategy to restore protective immunity during leishmaniasis, particularly in drug-resistant cases.