The area of antifungal agents, especially systemic agents used to treat life-threatening infections, has undergone rapid and significant change since 2000. The commercial availability of three echinocandins plus the addition of newer-generation triazole compounds has radically changed the landscape and management of invasive fungal infections. This review will focus primarily on the newer antifungal agents for systemic fungal infections that have become available since 2000. It will also address the role of the amphotericin B products in the current armamentarium, as many guidelines and authorities in the field still consider these agents to be first-line therapy.