Scedosporium apiospermum and Scedosporium prolificans cause therapy-refractory infections in immunocompromised and immunocompetent hosts. While innate immune response is believed to be critical for the host defense against these fungi, its role has only recently been elucidated. Undefined pathogen-associated molecular patterns on the surface of conidia and hyphae are recognized by pattern-recognition receptors (PRRs) on the membrane of phagocytes, and the signal is transmitted intracellularly. PRRs that are important in the recognition of both fungal species are human Toll-like receptors (or Toll receptors in Drosophila melanogaster) and dectin-1. These induce signals responsible for the activation of genes leading to an effective host defense, especially those encoding pro-inflammatory cytokines. Both species are efficiently phagocytosed and elicit an oxidative burst by neutrophils and monocytes. While cytokines, such as interleukin-15, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interferon-gamma, have been found in vitro to variably modulate antifungal activity of human phagocytes, cytokines in vivo activities are less well documented. Certain antifungal agents exert immunopharmacological effects on phagocytes against S. apiospermum and S. prolificans. Translation of these in vitro findings to appropriate in vivo systems and into clinical trials may lead to improved strategies for augmenting innate host defenses in patients infected with these emerging pathogens.