Invasive fungal infections (IFIs) are a significant cause of morbidity and mortality in severely immunocompromised hosts. There are now several new treatment options, including lipid forms of amphotericin B, azoles, and echinocandins, with improved tolerability profiles and novel mechanisms of action compared with conventional amphotericin B. Despite the expanding antifungal armamentarium, IFIs remain a common problem in patients at risk for invasive mycoses. The past 2 decades have seen an increase in the spectrum of opportunistic pathogens, including difficult-to-treat mold infections. The changing epidemiology of IFIs may be due to several factors, such as advances in therapy (new aggressive forms of immunosuppression and increased transplantation procedures) and emergence of resistance to antifungal drugs. The early diagnosis and treatment of patients with invasive infections present a significant challenge. This review will discuss epidemiological shifts, current therapeutic strategies to treat IFIs, and combination antifungal therapy with polyenes for the treatment of invasive mold infections.