The frequency of invasive fungal infections has increased dramatically in recent decades because of an expanding population at risk. Until now, treatment options for invasive mycoses have been primarily amphotericin B and the azoles, fluconazole and itraconazole. Traditional agents are limited by an inadequate spectrum of activity, drug resistance, toxicities, and drug-drug interactions. The recent approval of caspofungin and voriconazole clearly has expanded the number of existing antifungal drugs available. However, the enthusiasm that accompanies their availability is counterbalanced by limited clinical experience, high drug acquisition costs, and distinctive toxicities. The pharmacologic characteristics, extent of clinical experience (efficacy and toxicity), and drug acquisition costs among available systemic antifungal agents are compared, with emphasis on the new agents. Also, recommendations on the role of each agent are provided according to the most common indications for systemic antifungal therapy: invasive candidiasis, invasive aspergillosis, and febrile neutropenia.