Aspergillus species are ubiquitous fungal saprophytes found in diverse ecological niches worldwide. Among them, Aspergillus fumigatus is the most prevalent and is largely responsible for the increased incidence of invasive aspergillosis with high mortality rates in some immunocompromised hosts. Azoles are the first-line drugs in treating diseases caused by Aspergillus spp. However, increasing reports in A. fumigatus azole resistance, both in the clinical setting and in the environment, are threatening the effectiveness of clinical and agricultural azole drugs. The azole target is the 14-α sterol demethylase encoded by cyp51A gene and the main mechanisms of resistance involve the integration of tandem repeats in its promoter and/or single point mutations in this gene. In A. fumigatus, azole resistance can emerge in two different scenarios: a medical route in which azole resistance is generated during long periods of azole treatment in the clinical setting and a route of resistance derived from environmental origin due to extended use of demethylation inhibitors in agriculture. The understanding of A. fumigatus azole resistance development and its evolution is needed in order to prevent or minimize its impact. In this article, we review the current situation of azole resistance epidemiology and the predominant molecular mechanisms described based on the resistance acquisition routes. In addition, the clinical implications of A. fumigatus azole resistance and future research are discussed.