Although our antifungal armamentarium has been enlarged recently with new azoles (voriconazole and posaconazole) and echinocandins (caspofungin, micafungin, anidulafungin), the polyenes still have an important role in antifungal strategies because of their extended antifungal spectrum and rarity of mycological resistance. The use of conventional amphotericin B deoxycholate is limited by substantial toxicity that is either infusion-related or associated with renal failure. Its lipid derivatives, particularly liposomal amphotericin B (LAmB), are less nephrotoxic while maintaining a broad antifungal spectrum. LAmB is active against most Candida spp., including Candida glabrata and Candida parapsilosis, and against more resistant, emerging yeasts species such as Rhodotorula spp., Geotrichum spp. and Trichosporon spp.. LAmB is also active against Cryptococcus spp. and all dimorphic fungi such as Histoplasma, Blastomyces, Coccidioidomyces, and Paracoccidiodomyces. The antifungal spectrum of LAmB is particularly interesting with regard to filamentous fungi, with marked activity against Aspergillus spp. and agents of zygomycosis. The latter might emerge during long-term treatment with voriconazole or an echinocandin, as these organisms are resistant to these drugs. We review here the role of LAmB in the current antifungal management strategy, which is based on results obtained in prospective trials. LAmB can be retained as first-line treatment for human immunodeficiency virus (HIV)-positive patients with disseminated histoplasmosis and cryptococcosis, even in the setting of renal impairment or concomitant administration of potentially nephrotoxic drugs. In addition, there is sufficient evidence that the drug should be a major consideration for the empirical treatment of persistent febrile neutropenia or as an alternative to for patients with invasive aspergillosis, for those at risk of renal impairment, major drug-drug interaction or liver insufficiency, particularly in the situation of an established azole intolerance. The primary licensed indication for LAmB is empirical treatment. When zygomycosis is suspected or has been documented, high doses of LAmB should be prescribed. Finally, LAmB may also be considered as a therapeutic option for the management of candidaemia and remains a cornerstone for the treatment of some visceral localisations during systemic candidosis.