Invasive fungal infections (IFIs) remain an important cause of morbidity and mortality in patients with acute or chronic leukemia. Advances in the pharmacotherapy of fungal infections and a shift in the epidemiological characteristics of fungal pathogens toward fluconazole-resistant Candida species and saprophytic molds have placed a greater emphasis on selection of broader-spectrum agents for empirical therapy of IFIs in this high-risk population. Newer diagnostic modalities, such as the Aspergillus galactomannan test, the 1,3-beta-d-glucan test, and polymerase chain reaction detection of fungal DNA, may facilitate the earlier diagnosis of IFIs, but their role in detecting breakthrough infection and their usefulness as a marker to withhold antifungal therapy in high-risk leukemia patients with IFI are less obvious, especially in patients who are receiving antifungal prophylaxis. Only 2 strategies have been shown in prospective studies to improve survival from mold infection in patients with acute myelogenous leukemia or myelodysplastic syndrome: (1) preemptive initiation of antifungal therapy at first sign of invasive aspergillosis on computed tomography (CT) scan and (2) antifungal prophylaxis with posaconazole. CT-guided treatment decisions are more complex in patients with advanced leukemia, however, because of concomitant infection or relapsing malignancy. Similarly, posaconazole is often not a viable prophylaxis or treatment option in patients with poor oral intake, gastrointestinal dysfunction, or possible drug interaction (eg, proton pump inhibitor prophylaxis in patients on high-dose glucocorticosteroids). As a result, the management of IFI in patients with leukemia demands an individualized treatment plan.