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Infection with parasites of the genus Leishmania is a health problem in many countries around the world. No effective vaccine is available against leishmaniasis, so chemotherapy is the only alternative for treatment of all forms of the disease. However, drawbacks including toxicity and severe adverse reactions restrain the use of currently available chemotherapeutics. Therefore development of new drugs and therapeutic approaches is highly demanded. Mammalian host defense peptides (mHDP) and/or mammalian antimicrobial peptides (mAMP) are among promising compounds considered effective to control the infectious diseases. These are potential multifunctional molecules that modulate the immune response besides direct killing of pathogens. Here we have reviewed the hallmark characteristics of the mHDPs in respect to the potential role they can play against leishmaniasis., (Copyright © 2016 Elsevier Inc. All rights reserved.)