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Leishmania are protozoan parasites responsible for a spectrum of diseases collectively known as leishmaniasis. The disease is a significant health problem in many regions of the world and emerges as a serious co-infection in HIV-positive individuals. Current treatment of the disease is based on a limited number of chemotherapeutic agents which are rapidly becoming ineffective, and are characterized by high toxicity and cost. This review focuses on recent advances in antileishmanial drug development and improvements to current treatment options. Novel approaches currently used to identify leishmanicidal compounds as diverse as antimicrobial peptides and natural plant extracts are described in this review.