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Leishmaniases are considered among the most neglected yet dangerous parasitic diseases worldwide. According to the recent WHO report (Weekly Epidemiological Record, Sep, 2021), 200 countries and territories reported leishmanises cases in 2020; of which 89 (45%) for CL, and 79 (40%) for VL were endemic. Indian subcontinent (India, Bangladesh and Nepal), one of the three eco-epidemiological hotspots of VL, currently reported 18% of the total cases of VL worldwide. Eastern Mediterranean region and the Region of the Americas together reported >90% of the new CL cases, of which >80% were from Afghanistan, Algeria, Brazil, Colombia, Iraq, Pakistan and the Syrian Arab Republic. While considering the current therapeutic options, conventional anti-leishmanial drugs have long been proved to be toxic and/or expensive and have resulted in extensive drug resistance in India. Recent searches for novel anti-leishmanial drugs have led to find out the prime cellular targets and metabolic pathways to bridge the gap between the known facts and unexplored data. Cutting edge knowledge based drug designing has simplified the search for novel molecules with leishmanicidal efficacy by identifying ligand-receptor interactions and has accelerated the cost effective primary discovery of molecules through computational validation against Leishmaniases. This review focuses on the limitations of conventional drugs, and discusses the chemotherapeutic potential of many novel natural and synthetic anti-leishmanial agents reported since the last decade. It is also interpreted that some of the reported molecules might be tested singly or as a part of combinatorial therapy on pre-clinical and clinical level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)