Leishmaniasis represents a significant impact to the world due to its high prevalence and distribution, especially with regard to the most affected areas located in the Tropical, Subtropical, and Mediterranean regions. There are several challenges which currently impair the control of this disease in endemic areas, which are a result of the lack of health and social investment associated with the scarce scientific support towards the optimization of leishmaniasis diagnosis and treatment. The currently available drugs for the treatment of leishamiasis have problems which limit their use, including toxicity, high cost, and resistant Leishmania strains. Therefore, leishmaniasis treatment research is currently focused on the possible substitution of conventional treatment through the discovery of new compounds or the employment of new therapeutic regimens provided they become safer alternatives to the established protocols. Another promising alternative is the use of drug combinations; however, little progress has effectively been made in this context. Despite the recent research advances, the combat of leishmaniasis still faces the results of decades of stagnation in terms of therapeutic possibilities.