Randomized clinical trials in systemic antifungal therapy have traditionally been focused on patients with systemic candidiasis, cryptococcal meningitis, invasive aspergillosis and febrile neutropenic patients with suspicion of a fungal infection. The latter is a known risk factor for infection with filamentous fungi. Itraconazole and voriconazole are active against molds when compared with fluconazole but they are not active against agents of mucormycosis. Both itraconazole and voriconazole cover clinical isolates of Candida albicans and non C. albicans isolates with natural or acquired resistance to fluconazole. Although every triazole compound can be applied on infection caused by C. albicans, only fluconazole has been validated in this setting. Moreover, this compound is the only one approved for the treatment of patients affected by low-risk cryptococcal meningitis. In patients with invasive aspergillosis, only voriconazole has been formally compared and found similar to amphotericin B although open-label studies with intravenous itraconazole also demonstrate its usefulness in this condition. In contrast, in neutropenic febrile patients with suspicion of a fungal infection, intravenous itraconazole but not voriconazole has been shown equivalent to amphotericin B. Triazole compounds differ each other in their dosing schedules, bioavailability, interference of food or changes in gastric pH in absorption, penetration to the CNS, time to reach plasma steady-state concentrations and acquisition costs. Intravenous presentations of itraconazole and voriconazole should not be administered when moderate or mild renal failure is present (< 30 vs < 50 ml/min of creatinine clearence, respectively).