Invasive infections due to filamentous fungi, such as Aspergillus spp., Zygomycetes, Scedosporium and Fusarium spp., cause significant morbidity and mortality in immunocompromised patients with hematological malignancies, recipients of hematopoietic stem cell transplants and those with chronic granulomatous disease. Despite antifungal therapy, the outcome is often unfavorable in these patients; immune restoration is considered as the cornerstone of successful treatment. Important aspects of human immune response against fungi include effective innate immune response expressed as effective phagocytic functions and a balance between proinflammatory and regulatory adaptive immune responses. A number of immunomodulatory approaches, including the administration of enhancing cytokines, adoptive transfer of pathogen-specific T lymphocytes and granulocyte transfusions have been investigated as adjunctive treatments against serious mold infections. Despite encouraging in vitro and in vivo data, current clinical evidence is not sufficient to allow firm recommendations on the use of these immunomodulatory modalities in serious mold infections.