Leishmaniasis is a diverse group of neglected diseases caused by protozoan parasite of genus Leishmania and transmitted by the bite of a female phlebotomine sand fly. These diseases stand as a major health problem worldwide, especially in their visceral form. Despite innumerable studies on leishmaniasis, many questions are still unanswered. One of the main challenges is the presence of different Leishmania species and various clinical manifestations, complicating the therapeutic approach. There are many available antileishmanial agents, but the drug of choice is still out of reach, since almost all available drugs share several limitations and many of them are expensive with severe side effects or have a markedly reduced effectiveness. Immunosuppressed patients should also be given a special attention which represents an additional challenge. In the meantime, the combination of local and parenteral therapies with existing drugs remain a priority to improve the efficacy and to shorten the duration of the treatment. This review was undertaken to highlight the chemotherapeutic strategies, their mechanisms of action and main limitations.