The availability of new antifungal agents with novel mechanisms of action and improved tolerability has widened the possibilities for combination therapy for difficult-to-treat opportunistic mycoses. However, empiricism largely governs this therapy, especially in patients with invasive mould infections for whom there is a dire need to improve outcomes. Because of difficulties associated with the design and conduct of clinical trials of combination therapy for opportunistic mycoses, most studies are still performed in the laboratory or in animal models. Methods to assess combined antifungal effects in vitro and in animals are poorly standardized, and little evidence suggests that the data generated from these studies are relevant to treating. patients. Even without solid evidence to support routine combination therapy, certain principles can guide its use in select patients.