Gastrointestinal cancers are responsible for more cancer deaths than any other system of the body. This review summarises how Wnt pathway dysregulation contributes to the development of the most common gastrointestinal cancers, with a particular focus on the nature and frequency of upstream pathway aberrations. Tumors with upstream aberrations maintain a dependency on the presence of functional Wnt ligand, and are predicted to be tractable to inhibitors of Porcupine, an enzyme that plays a key role in Wnt secretion. We summarise available pre-clinical efficacy data from Porcupine inhibitors in vitro and in vivo, as well as potential toxicities and the data from early phase clinical trials. We appraise the rationale for biomarker-defined targeted approaches, as well as outlining future opportunities for combination with other therapeutics.