Pathogenic fungi are the cause of life-threatening infections in an increasing number of immunocompromised patients. The intrinsic resistance to antifungal therapy observed in some genera, along with the development of resistance during treatment in others, is becoming a major problem in the management of these diseases. We reviewed the epidemiology of the most common systemic fungal infections for which antifungal resistance is a potential problem, the mechanisms of antifungal resistance, the correlation between in vitro susceptibility testing and clinical outcome, and the clinical implications of antifungal resistance.