Cystic fibrosis (CF) is a human genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene that encodes a chloride channel. The most severe clinical manifestation is associated with chronic pulmonary infections by pathogenic and opportunistic microbes. Drosophila melanogaster has become the invertebrate model of choice for modeling microbial infections and studying the induced innate immune response. Here, we review its contribution to the understanding of infections with six major pathogens associated with CF ( Staphylococcus aureus , Pseudomonas aeruginosa , Burkholderia cepacia , Mycobacterium abscessus , Streptococcus pneumoniae, and Aspergillus fumigatus ) together with the perspectives opened by the recent availability of two CF models in this model organism.