Concurrent or sequential antifungal treatment for invasive mycoses has been typically considered as an option to improve results of monotherapy. However, data on the efficacy of combination therapy are sparse and consist largely of results from studies in vitro and experimental animal models. These studies have yielded controversial results depending on the criteria used to evaluate the antifungal interaction. Several combinations that showed synergy in vitro failed to do so in animal models. Overall, apart from cryptococcal infections, combined antifungal therapy is not significantly better than monotherapy in terms of clinical efficacy. It is questionable whether combination therapy should be used in most cases as there is a lack of evidence from well-designed clinical trials. However, combination therapy could be an alternative to monotherapy for patients with invasive infections that are difficult to treat, such as those due to multi-resistant species and for those who fail to respond to standard treatment.