Determining the optimal polyene antifungal dosing in obese patients is considered highly challenging. Limited data are available to describe the pharmacokinetics of polyene antifungals in these patients. However, polyene antifungals demonstrate widely variable pharmacokinetics in various clinical conditions. In particular, the two main parameters that define dosing requirements, volume of distribution (V) and clearance, can change significantly in obese patients. Therefore, in the absence of robust data to describe optimal polyene dosing in obesity, dosing guided by therapeutic drug monitoring (TDM) remains the best approach, particularly when aggressive dosing is required in the context of poorly susceptible pathogens. Lean body weight appears to be the preferred weight metric to estimate polyene dosing in obesity, in order to prevent inappropriate excessive doses and subsequent adverse events including nephrotoxicity