One of the most recently described familial colorectal cancer (CRC) syndromes involves patients with cystic fibrosis (CF), who are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients (of which there are ~ 3500 CF cases currently in Australia) will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new cystic fibrosis colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients. The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US, and ~ 1 million in Australia) who are heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where it’s downregulation is associated with poor survival, a phenomenon linked to epigenetic gene silencing in other cancers such as lung cancer. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/b-catenin signaling, intestinal stem cell homeostasis, intestinal barrier integrity, intestinal dysbiosis, immune cell infiltration, epigenetic gene silencing, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers. Here, we will describe our research into the role of CFTR dysregulation in GI cancer using a conditional mouse model of CF and analysis of human CRC tissues. There will be updated data on a potential role for CFTR in regulating oxidative stress in the intestinal stem cell compartment, as well as other potential mechanisms.