The clinical treatment of leishmaniasis is based on a limited number of drugs, which are associated with adverse effects and have already induced resistance. Amphotericin B (AmB), a polyene antibiotic produced by Streptomyces sp, is the only anti-leishmanial drug which has not induced clinical resistance since its discovery in 1956. The limiting factor in the use of AmB is its toxic effects, mainly nephrotoxicity. The maximal dose of AmB for human use is 1.5 mg/kg which sometimes is not sufficient for cure. The mode of action of AmB is associated with its toxicity: it selectively binds to parasite membrane ergosterol but also, to a lesser extent, to human cholesterol. Apart from this mechanism, AmB has immunomodulatory effects, some of them are deleterious. Reduction of the toxic effects by using lipid formulations allows the infusion of higher doses of AmB. Unfortunately, these formulations are relatively expensive and therefore out of reach for patients in need, in the endemic areas. All the existing formulations are given parenterally, which has obvious disadvantages; most important is the need for hospitalization or multiple visits in the clinic. The current efforts to improve AmB are directed at the production of AmB aggregates in liquid solutions, encapsulation with lipid components, and solubilization by binding to soluble polymers. The expected improved treatment resulting from use of the new formulations is based on better pharmacokinetics, reduced toxicity originating from slow release, targeting to the infected organ and an altered pattern of immune responses (related to AmB). Of particular importance are the attempts to produce derivatives for oral treatment, which will decrease costs of hospitalization and improve applicability for children and the elderly population.