Based on systematic review and meta-analysis, the risk for developing cancers in patients with cystic fibrosis (CF) is known to be significantly greater than in the general population, including site-specific cancers of the esophagus, small bowel, colon, liver, biliary tract, and pancreas. An even higher risk has been found in patients who have severe CF transmembrane conductance regulator (CFTR) genotypes or who have undergone organ transplantation and are immunosuppressed. The risk continues to rise as life expectancies steadily climb due to advancements in medical care and treatment for CF. The colorectal cancer risk is at such a high level that CF has now been declared a hereditary colon cancer syndrome by the Cystic Fibrosis Foundation. The CFTR gene has been strongly-associated with the development of gastrointestinal (GI) cancers and mortality in the CF population. Even CF carriers have shown an increased rate of GI cancers compared to the general population. Several limitations exist with the reported guidelines for screening of GI and hepatopancreatobiliary cancers in the CF population, which are largely universal and are still emerging. There is a need for more precise screening based on specific risk factors, including CFTR mutation, medical co-morbidities (such as gastroesophageal reflux disease, distal intestinal obstruction syndrome, and diabetes mellitus), familial risks for each cancer, gender, age, and other factors. In this review, we propose changes to the guidelines for GI screening of patients with CF. With the development of CFTR modulators, additional studies are necessary to elucidate if there is an effect on cancer risk.