Purpose of Review The purpose of this review is to assess the recommended treatment regimens for the major endemic mycoses, histoplasmosis and blastomycosis, which occur in the Midwestern USA and to provide information about the use of newer antifungal agents for these diseases. Recent Findings The basic approach to treatment of histoplasmosis and blastomycosis outlined in the IDSA Guidelines is helpful in managing these diseases. However, changes since these guidelines were published provide safer and better tolerated treatment regimens. Prolonged treatment with amphotericin B is rarely required, and lipid formulations of this drug have largely replaced the amphotericin B deoxycholate formulation. Although no clinical trials have been performed and the data are anecdotal, voriconazole and posaconazole are increasingly used in patients who cannot tolerate itraconazole. Voriconazole is especially useful when central nervous system infection is present. Posaconazole tablets provide consistently appropriate serum levels and the drug is well tolerated. Summary New azole agents provide alternative therapeutic options for histoplasmosis and blastomycosis.