The introduction of the azole class of antifungal drugs with the licensing of miconazole in 1979 marked the beginning of a new era in therapy for systemic fungal diseases. Although miconazole, an intravenous formulation associated with significant toxicity, is no longer commercially available, it set the stage for the development and subsequent licensing of three oral azole drugs: ketoconazole, fluconazole, and itraconazole . For many systemic mycoses, these drugs have been effective and safe alternatives to the older antifungal drugs - amphotericin B, a member of the polyene class and for years the so-called gold standard of therapy, and flucytosine, a fluorinated pyrimidine. Ketoconazole, introduced in 1981, fluconazole (1990), and itraconazole (1992) have been attractive agents because of their excellent spectrum of activity against Candida species and endemic fungi and their overall efficacy, safety, and ease of oral administration. However, these drugs for the most part lack significant activity against mould pathogens, an important group of emerging opportunistic fungi. Consequently, the past several years have -witnessed the development of an exciting group of second-generation triazole drugs, which possess an expanded spectrum of activity, especially against various moulds and resistant Candida species. Voriconazole, approved in 2002, is the first of these to become commercially available; posaconazole was most recently licensed - in 2006 [2, 3]. Our purpose in this chapter is to compare and contrast the pharmacologic properties of the older oral azoles and the newer triazoles and to provide perspective on the clinical indications for these agents. Since ketoconazole is the oldest azole and now the least used, our comments about ketoconazole will be limited.