Leishmaniasis treatment has faced challenges with pentavalent antimonials, historically used but now showing resistance and high failure rates. The World Health Organization (WHO) recommended higher doses, but resistance in Nepal and misuse persist. Antimonials are no longer the preferred treatment for visceral leishmaniasis (VL) in the Indian subcontinent but are still used for cutaneous leishmaniasis (CL). Amphotericin B, especially liposomal amphotericin B (L-AmB), has become the preferred treatment for VL in the Indian subcontinent, with high efficacy and shorter treatment courses. Genetic insights into leishmaniasis reveal that parasite species and host immune responses are key factors in disease variation. Genetic analysis of atypical parasite isolates shows that genetic variations can lead to different disease patterns. Whole genome sequencing and proteomic analyses offer fresh insights into how parasite genes and proteins impact drug resistance, post-kala-azar dermal leishmaniasis (PKDL), and unusual disease presentations. Variations in hereditary unit copy numbers and single nucleotide polymorphisms contribute to genetic diversity and distinct tissue distribution, leading to distinct disease patterns. Genomic markers for drug resistance in Leishmania parasites include ATP-binding cassette (ABC) transporters, amino acid permease 3 (AAP3), and proteins like phosphoglycerate kinase (PGK) and mitogen-activated protein kinase (MAPK). These markers are associated with efflux of thiols and metals, antimony resistance, and protection against oxidative stress. Additionally, key proteins and enzymes in antioxidant defense mechanisms, such as iron superoxide dismutase-A (FeSOD-A), folate transporter 1 (FT1), and heat shock protein 83 (HSP83), play roles in drug resistance and parasite survival.