Amphotericin B (AmB) is considered the drug of choice for the treatment of systemic fungal infections. Nephrotoxicity is a major complication associated with its use, and appears to be related to higher cumulative doses, diuretic use, abnormal serum creatinine at baseline, and the use of concomitant nephrotoxic drugs. The two major hypotheses for the pathogenesis of AmB-related nephrotoxicity are direct effects of the drug on epithelial cell membranes and vasoconstriction. During the last few years, some randomized trials have tested different strategies to reduce AmB-induced renal toxicity. These strategies include sodium supplementation, low-dose dopamine, slower infusion rates, the administration of AmB in lipid emulsions, and in lipid formulations. The results of these trials showed that the lipid formulations of AmB significantly reduce nephrotoxicity. Unfortunately, these agents are costly, restricting their use to patients with a high risk of developing renal failure.