The prognosis for persons with invasive fungal infections has improved over the past 2 decades because of the development of new diagnostic tools, a better understanding of the epidemiology and prognostic factors of these infections, and the availability of new antifungal agents. Nevertheless, antifungal therapy failure is still a substantial clinical problem. When this occurs, the clinician is tempted to attribute therapeutic failure to specific drug resistance and then to change therapy or add another antifungal drug to the regimen. However, other factors may play an even greater role in antifungal therapy failure, such as host factors, low concentration of the drug at the site of infection, drug toxicities, wrong diagnosis, and misdiagnosis of failure because of the occurrence of immune reconstitution inflammatory syndrome. In this review, we discuss the differential diagnosis and management of antifungal therapy failure in invasive mycoses, to help clinicians appreciate the meaning of primary antifungal therapy failure.