In recent years, several drugs have been approved that specifically target molecular changes in tumour cells. For patients with gastrointestinal cancer, this has contributed to a significant improvement in prognosis. This article provides an overview of the currently available treatment options and the underlying biomarkers of their mechanisms of action.The evaluation of biomarkers and the use of targeted therapeutics have now become standard care in gastrointestinal oncology. Beyond the molecular-targeted therapy options already approved in the European Union, there is a multitude of additional drugs and biomarkers available, which can also be used outside of formal approval (so-called off-label use). Examples of this are also discussed in this overview (e.g., HER2-targeted therapy for cholangiocarcinoma, the use of KRAS G12C inhibitors, or checkpoint inhibition in microsatellite unstable ductal pancreatic carcinoma).The question whether the use of one of these therapeutics represents a possible treatment option for patients with gastrointestinal cancers is typically discussed in a Molecular Tumour Board after undergoing guideline-appropriate therapies.