Drug resistance in leishmaniasis is a growing concern, affecting both treatment efficacy and public health. Leishmaniasis is caused by 17 species of Leishmania parasites, transmitted by sandflies. It affects humans and animals, with different clinical forms including visceral (VL), cutaneous (CL), and mucocutaneous (MCL) leishmaniasis. VL is primarily found in Sudan, while CL is prevalent in regions like Afghanistan, Syria, and Brazil. The disease is a global health issue, with an estimated 12 million cases, though the actual number may be underestimated. Current treatments for leishmaniasis include antimonials, amphotericin B, miltefosine, pentamidine, paromomycin, and azoles. However, drug resistance is emerging, particularly with antimonials, which are widely used for VL. Resistance is influenced by factors such as species variation, pharmacokinetics, immune status, and drug-host interactions. For example, L. donovani is more sensitive to antimonials than other species, but resistance has been reported in some regions, such as North Bihar, India. The development of resistance is also linked to improper drug use, including incorrect dosing, incomplete treatment, and lack of supervision. In some cases, resistance has been observed in patients with HIV/VL coinfections, where immune status plays a critical role. Additionally, resistance can develop due to the long-term use of antimonials as monotherapy, especially in areas with high transmission rates. Mechanisms of resistance include reduced drug uptake, increased efflux, and changes in drug targets. For example, resistance to amphotericin B is associated with changes in sterol profiles, while resistance to miltefosine involves reduced drug accumulation and the presence of specific transporters. Resistance to paromomycin and azoles is linked to altered drug uptake and efflux mechanisms. New drugs and formulations are being developed to combat resistance, including liposomal amphotericin B, oral miltefosine, and sitamaquine. Combination therapies and resistance reversal agents are also being explored. Monitoring drug resistance is crucial for effective treatment and public health control. The study highlights the need for improved diagnostic methods, better drug distribution, and the development of new targets and drugs to address the growing challenge of drug resistance in leishmaniasis.Drug resistance in leishmaniasis is a growing concern, affecting both treatment efficacy and public health. Leishmaniasis is caused by 17 species of Leishmania parasites, transmitted by sandflies. It affects humans and animals, with different clinical forms including visceral (VL), cutaneous (CL), and mucocutaneous (MCL) leishmaniasis. VL is primarily found in Sudan, while CL is prevalent in regions like Afghanistan, Syria, and Brazil. The disease is a global health issue, with an estimated 12 million cases, though the actual number may be underestimated. Current treatments for leishmaniasis include antimonials, amphotericin B, miltefosine, pentamidine, paromomycin, and azoles. However, drug resistance is emerging, particularly with antimonials, which are widely used for VL. Resistance is influenced by factors such as species variation, pharmacokinetics, immune status, and drug-host interactions. For example, L. donovani is more sensitive to antimonials than other species, but resistance has been reported in some regions, such as North Bihar, India. The development of resistance is also linked to improper drug use, including incorrect dosing, incomplete treatment, and lack of supervision. In some cases, resistance has been observed in patients with HIV/VL coinfections, where immune status plays a critical role. Additionally, resistance can develop due to the long-term use of antimonials as monotherapy, especially in areas with high transmission rates. Mechanisms of resistance include reduced drug uptake, increased efflux, and changes in drug targets. For example, resistance to amphotericin B is associated with changes in sterol profiles, while resistance to miltefosine involves reduced drug accumulation and the presence of specific transporters. Resistance to paromomycin and azoles is linked to altered drug uptake and efflux mechanisms. New drugs and formulations are being developed to combat resistance, including liposomal amphotericin B, oral miltefosine, and sitamaquine. Combination therapies and resistance reversal agents are also being explored. Monitoring drug resistance is crucial for effective treatment and public health control. The study highlights the need for improved diagnostic methods, better drug distribution, and the development of new targets and drugs to address the growing challenge of drug resistance in leishmaniasis.