Leishmaniasis is one of the six entities on the list of most important diseases of the World
Health Organization/Tropical Disease Research (WHO/TDR). After Malaria, it is one of the most
prevalent and lethal parasitic diseases. VL is the fatal form of this disease, especially if left untreated.
The drugs that are currently available for the treatment of VL are expensive, toxic, or no longer effective,
especially in endemic regions. Currently, no vaccine has been developed to immunize humans
against VL. The major problems with the current drugs are the development of resistance and their
adverse effects. Therefore, there is a strong urge to research and design drugs that have better efficacies
and low toxicities as compared to current chemotherapeutic drugs. Leishmania has various enzymes
involved in its metabolic pathways, which are unique to either the same genus or trypanosomatids,
making them a very suitable, attractive and novel target sites for drug development. One of the
significant pathways unique to trypanosomatids is the thiol metabolism pathway, which is involved in
the maintenance of redox homeostasis as well as protection of the parasite in the macrophage from oxidative
stress-induced damage. In this review the several pathways, their essential enzymes as well as
the proposed changes in the parasites due to drug resistance have been discussed to help to understand
the most suitable drug target. The thiol metabolism pathway is discussed in detail, providing evidence
of this pathway being the most favorable choice for drug targeting in VL.