For over the last three decades, extensive testing of antifungal compounds in clinical trials has been essential to the development of treatment guidelines for the most common invasive fungal infections, including cryptococcosis, candidiasis, aspergillosis, and the endemic fungi. These guidelines have greatly helped guide clinicians in the management of these complicated diseases. The data on which most of these guidelines are based are among the most widely recognized and cited clinical trials comparing antimicrobial agents. Unfortunately, there are many unanswered questions with respect to the diagnosis and treatment of these emerging disorders. Regarding treatment, there is a need for more clinically effective and less toxic agents. The current armamentarium of antifungal agents represents important progress over gold standard agents such as amphotericin B, but there is much progress to be made. With respect to diagnostics, mycology has generally lagged behind other disciplines in microbiology, as there are very fewrapid, sensitive, specific, and point-ofcare diagnostics. The ability to implement therapies for at-risk patients based on positive early diagnostic signals would greatly enhance the ability to intervene with appropriate antifungal therapy in a more targeted and specific manner. This article will review some of the major advances, as well as significant challenges that remain in the management of invasive mycoses.