Objectives: Species from the Scedosporium apiospermum complex rank the second among the filamentous fungi colonizing the respiratory tract of cystic fibrosis (CF) patients. Nevertheless, the pathogenesis of Scedosporium infections remains poorly understood. Notably, the mechanisms developed by these molds to establish within the bronchial tree are still unknown. Among the species from the S. apiospermum complex, four have been identified as capable to chronically colonize the CF respiratory tract (S. boydii, S. apiospermum, S. aurantiacum ,and S. minutisporum) whereas S. dehoogii , which is common in the environment is unable to establish chronically in the lungs of CF patients. Since several years, we aimed at identifying the key molecular mechanisms underlying the ability of Scedosporium species to establish within the respiratory tract of CF patients and to cause chronic colonization of the airways. Methods: To identify candidate genes potentially involved in the adaptation and pathogenicity of Scedosporium species, we recently performed two complementary omics approaches including transcriptomics and comparative genomics. First, the transcriptome of the S. apiospermum reference strain (IHEM14462) was compared in different growth conditions mimicking the various physio-chemical constraints encountered in the respiratory tract of CF patients (hypercapnia, hypoxia, acid pH, low osmolarity, increased lactate concentration). For the comparative genomic strategy, we sequenced 5 isolates from each of the five species S. boydii, S. apiospermum, S. aurantiacum, S. minutisporum, and S. dehoogii . To identify candidate proteins that may enable Scedosporium species to establish within the respiratory tract of CF patients, we first searched clusters of orthologous proteins with no copy found in S. dehoogi isolates but conserved in all other isolates. In a second time we also detected genes present in all pathogenic species, as well as in S. dehoogii but exhibiting in this last species point mutations potentially leading to a loss of function. Results: As revealed by the transcriptomic approach, while hypercapnia, increased lactate or low osmolarity modified the expression of a limited number of genes, the transcriptome of S. apiospermum was greatly influenced by hypoxia, growth at acid pH or in a cystic fibrosis synthetic medium. In addition, the whole-genome sequencing project of several isolates from the five Scedosporium species allowed to obtain a total of 2.4-8.9 mega-reads per isolate which permitted good quality draft genome assemblies. Finally, comparative genomics allowed to identify a series of 134 genes lost or with a loss of function in S. dehoogii but still functional in all other species. Conclusion: The transcriptomic changes observed during S. apiospermum exposure to the physico-chemical conditions en-countered in the respiratory tract of cystic fibrosis patients as well as the set of candidate genes revealed by the comparative genomic strategy would help deciphering in a near future the crucial mechanisms allowing these opportunistic pathogens to specifically adapt to the CF bronchial mucus.