Pseudomonas aeruginosa has long been established as the most prevalent respiratory pathogen in Cystic Fibrosis (CF) patients, with opportunistic infection causing profound morbidity and mortality. Recently, Aspergillus fumigatus has also been recognised as a key contributor to CF lung deterioration, being consistently associated with decreased lung function and worsened prognosis in these patients. As clinical evidence for the common occurrence of combined infection with these two pathogens increases, research into the mechanism and consequences of their interaction is becoming more relevant. Clinical evidence suggests a synergistic effect of combined infection, which translates into a poorer prognosis for the patients. In vitro results from the laboratory have identified a variety of possible synergistic and antagonistic interactions between A. fumigatus and P. aeruginosa. Here, we present a comprehensive overview of the complex environment of the CF lung and discuss how it needs to be considered to determine the exact molecular interactions that A. fumigatus and P. aeruginosa undergo during combined infection and their effects on the host.