Arastehfar, ACarvalho, AHoubraken, JLombardi, LGarcia-Rubio, RJenks, JDRivero-Menendez, OAljohani, RJacobsen, IDBerman, JOsherov, NHedayati, MTIlkit, MArmstrong-James, DGabaldón, TMeletiadis, JKostrzewa, MPan, WLass-Flörl, CPerlin, DSHoenigl, M2023-08-012023-08-012021-090166-06161872-9797https://hdl.handle.net/10161/28606The airborne fungus <i>Aspergillus fumigatus</i> poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant <i>A</i>. <i>fumigatus</i> isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in <i>CYP</i> <i>51A</i> are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type <i>CYP</i> <i>51A</i> genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant <i>A</i>. <i>fumigatus</i> isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against <i>A</i>. <i>fumigatus</i>. This review paper comprehensively discusses the current clinical challenges caused by <i>A</i>. <i>fumigatus</i> and provides insights on how to address them.Aspergillus fumigatusAzole-resistanceDrug-resistance mechanismInvasive aspergillosisJournal article2023-08-01