Aminoglycosides are one of the mainstays of antibiotic therapy in CF. They are administered parenterally in synergistic combinations with β-lactam antibiotics for acute exacerbations and used by inhalation as single agents for chronic maintenance therapy. It is well known in CF and other chronic infections that chronic use of antibiotics results in resistance. Thus, the increasing use of aminoglycosides could have dramatically changed the microbiological epidemiology of CF, since it was last examined a decade ago. It will be important to determine the current prevalence of antibiotic resistance in CF pathogens. Current antimicrobial strategies may also be contributing to the increased rate of isolation of novel and difficult to treat organisms, including intrinsically antibiotic-resistant bacteria. These issues are important both for CF clinicians and for researchers developing new antimicrobials to be used in CF.