The challenges in the treatment of systemic fungal infections after HSCT include: (1) changing epidemiology as less drug-susceptible saprophytic fungi are increasingly associated with human disease; (2) the difficulty of early and correct diagnosis, even with the new generation of enzymatic immunoassays; (3) the inability to reduce or eliminate predisposing factors, especially severe immune suppression in most transplant patients with these infections and (4) the uncertain role of antifungal drug combinations and risk of drug antagonism complicating effective empiric-pre-emptive therapy. Current, developing and future immune enhancement strategies including recombinant granulocyte- and granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), adjuvant pro-inflammatory cytokine therapy during mobilized donor granulocyte transfusions, therapeutic potential of pentraxin, adaptive immune transfer and dendritic cell fungal vaccines. Improved understanding of the molecular pathogenesis of fungal infections and of the complexity of host antifungal immune responses has provided the critical information to readdress existing treatment paradigms and further evaluate the role of GM-CSF and IFN-gamma early in the course of therapy against life-threatening fungal infections in high-risk patients following stem cell transplantation.