The gastrointestinal (GI) microbiome is shaped by host diet, immunity, and other physicochemical characteristics of the GI tract, and perturbations such as antibiotic treatments can lead to persistent changes in microbial constituency and function. These GI microbes also play critical roles in host nutrition and health. A growing body of evidence suggests that the GI microbiome in people with CF is altered, and that these dysbioses contribute to disease manifestations in many organs, both within and beyond the GI tract. Therapies that people with CF receive, even those targeting the respiratory tract, may impact the CF GI microbiome in ways that can influence the outcome of treatment. These new perspectives on the microbial contents of the CF intestine offer new opportunities for preventing a variety of CF‐associated disorders. Pediatr Pulmonol. 2016;51:S35–S44. © 2016 Wiley Periodicals, Inc.