en Microbial pathogenesis Microbial pathogenesis Mini Review Mini Review <div style="text-align: justify;"><span style="font-size:10.0pt"><span style="line-height:107%"><span new="" roman="" style="font-family:" times="">Leishmaniasis is a neglected tropical disease (NTD) that remains a significant global health challenge. While a small number of drugs are clinically effective, their use is constrained by toxicity, high cost, and emerging drug resistance. Furthermore, no licensed human vaccine is currently available. <i>Leishmania</i> exhibits extensive genomic plasticity, primarily through aneuploidy, gene copy number variations (CNVs), and subtelomeric amplifications, which confer remarkable flexibility and rapid adaptation to adverse environments, such as those encountered within the host or during drug treatment. Moreover, the extensive genetic diversity and plasticity of <i>Leishmania</i> enable it to rapidly adjust gene expression in response to environmental changes, facilitating adaptation to various stressors, including host immune responses and drug exposure. This adaptability significantly complicates effective treatment. In addition to vertical gene transfer, genetic exchange through hybridization and karyotypic instability are well-documented mechanisms that enhance the parasite&#39;s capacity to adapt to environmental stress. The role of horizontal gene transfer remains under investigation. This mini-review highlights the unique genomic features of <i>Leishmania</i>, particularly its genetic flexibility and unconventional mechanisms of gene expression<b> </b>regulation, such as aneuploidy and CNVs. It also examines major genetic manipulation tools used to investigate parasite biology, while discussing their inherent limitations. Understanding gene function is essential yet remains challenging due to the parasite&#39;s atypical genome organization and regulatory mechanisms. A deeper comprehension of <i>Leishmania</i> genetics is therefore crucial for the rational design of effective drugs and vaccines.</span></span></span></div> Leishmaniasis, Leishmania, Genetic diversity, Genomic plasticity, Treatment, Vaccine, Gene manipulation 240 245 http://jommid.pasteur.ac.ir/browse.php?a_code=A-10-441-12&slc_lang=en&sid=1 Tahereh Taheri Tahereh_t@yahoo.com 0000-0002-2619-6879 Yes Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran, Tehran, Iran