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Throughout the world, pentavalent antimonial compounds (Sbv) have been the mainstay of antileishmanial therapy for more than 50 years. Sbv has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6–10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sbv was eventually raised to 20 mg/kg for 30–40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sbv has steadily increased. In hyperendemic districts of north Bihar, 50–65% patients fail treatment with Sbv. Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sbv resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3–5 times more Sbv to reach similarly effectiveness against the parasite as in Sbv responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sbv refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69–78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sbv. The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.