Filamentous fungi especially Aspergillus spp. and Scedosporium spp. can colonize the lungs of cystic fibrosis (CF) patients. Persistent infection by these organisms may cause deterioration of lung function, mycetomas or local invasive disease. Although CF patients exert an excessive inflammatory response to inhaled bacteria, very little is known about the local innate immune response to filamentous fungi. In this paper, we review the innate immune response of respiratory tract of healthy individuals to filamentous fungi with some inference to CF patients and link the latter to existing data. We also report some preliminary findings on the in vitro antifungal responses of human phagocytes against Aspergillus spp. isolated from CF patients. Translation of these in vitro findings to appropriate in vivo systems and into clinical trials of immunomodulatory treatments may lead to improved strategies for appropriate innate host defenses in CF patients persistently infected with filamentous fungi.