The incidence of candidemia—a common and potentially fatal nosocomial infection—has risen dramatically, and this increase has been accompanied by a shift in the infecting pathogen away from Candida albicans to treatment-resistant non-albicans species. Prophylactic azole antifungals, such as fluconazole, may play an important role not only in the management of candidemia but also in the proliferation of hard-to-treat Candida species. In a variety of acute nosocomial settings, IV fluconazole, 400 mg/d, has reduced Candida colonization and infection. A growing body of evidence supports the still controversial contention that the increasing use of azole antifungals is at least partially responsible for the proliferation of treatment-resistant, non-albicans isolates, especially Candida glabrata. Thus, selecting the most appropriate candidates for prophylactic antifungal intervention—ie, those with the highest risk for candidemia—may be indispensable, not only in preventing candidemia, but also in reducing antifungal overuse, which may contribute to the emergence of treatment-resistant Candida isolates.