Amphotericin B deoxycholate (AmBD) was introduced 45 years ago for the treatment of invasive mycoses, on the basis of open-label non comparative data. Throughout these years of use it proved to be a life-saving drug but also a toxic compound which under current approval criteria might not meet licensing requirements. It still remains the gold standard of therapy for the broader spectrum of invasive mycoses, and exhibits the least potential for resistance. It is the drug used as comparator agent in clinical trials to test new antifungal agents. The three lipid based formulations of amphotericin B (LFABs) were created in an effort to overcome the toxicity of AmBD (nephrotoxicity and infusion related toxicity) and represent a significant advance in drug delivery technology. They have different physicochemical and pharmacokinetic properties, which have not yet found their clinical relevance. Clinically they have not proved more efficacious than the parent drug despite the advantage of administration in higher doses, but they have proved to be significantly less nephrotoxic. Few comparative studies of lipid products have been conducted. Liposomal amphotericin B (LAmB) is better tolerated with respect to infusion related events and can be infused in a shorter time. Amphotericin B colloidal dispersion (ABCD) has limited acceptance among clinicians because of the number of infusion related events. More head to head clinical trials are needed to check if one formulation is better than the others. Appropriate dosing is still open for LAmB and the role of LFABs as comparator drugs in clinical trials is emerging. The cost effectiveness of their use needs still remains to be demonstrated. In this paper, their role in combination antifungal therapy is investigated as well as new modes of administration (i.e. aerosolized).