Combination antifungal therapy has been an area of research and clinical interest since systemic antifungals became available decades ago. In vitro and clinical data were generated for some of the more common invasive fungal infections, especially candidiasis, but until very recently few clinical studies were performed. The first invasive fungal infection to be examined in clinical trials with adequate statistical power was cryptococcal meningitis and several of these trials stand out as classical studies in the clinical evaluation of combination antifungal therapy. More recently, since the availability of the newer antifungal agents, including the echinocandins and extended-spectrum triazoles, there has been a growing interest in examining combination antifungal therapy for invasive fungal disease, especially invasive aspergillosis. This is by no means a comprehensive review of all existing experimental data. Instead, the focus is on the clinical data that have been generated to date and on providing insights into potential future clinical directions. For instance, recent clinical data for cryptococcosis confirm that amphotericin B plus flucytosine is the most active combination for patients with cryptococcal meningitis. A recently completed clinical trial in candidaemia suggests a trend towards improved outcomes among patients receiving amphotericin B plus fluconazole versus fluconazole alone. In aspergillosis, several experimental models suggest benefit of a variety of antifungal combinations, but have not been confirmed in prospective clinical trials. Ultimately, the goal is to provide the reader with a comprehensive but useful review to this complicated and often confusing therapeutic dilemma. © 2005 Adis Data Information BV. All rights reserved.