<p>Children, adolescents, and young adults receiving intensive chemotherapy for acute myeloid leukemia or high-risk or relapsed acute lymphoblastic leukemia sustain prolonged periods of neutropenia that predispose them to invasive fungal disease (IFD). For many decades the standard of care for these patients was to initiate empirical antifungal therapy after a period of prolonged fever and neutropenia. Recent publications have yielded important evidence on the utility of different diagnostic and therapeutic approaches aimed at reducing the impact of IFD among these patients during these vulnerable periods. This case-based review highlights and interprets the published data to provide context for the IFD diagnostic and therapeutic recommendations proposed in multiple published guidelines. Personalized approaches are offered at points where evidence is lacking. Time points where specific knowledge gaps exist are identified along the clinical trajectory of the prolonged neutropenic period to illustrate areas for future investigation.</p>