Personalized tumor therapy or more precisely tumor-specific therapy has now become established in routine clinical oncology. Particularly for solid tumors, the emerging knowledge about pathways and signaling networks allows the establishment of new targeted therapies and hopefully a continuous improvement in patient care. Targeted therapies are now established as the standard of care as single agents or in combination with chemotherapy. Using targeted therapies, substantial improvements regarding tumor response, median progression-free survival and median overall survival can be achieved for selected gastrointestinal tumors. However, these strategies also have novel side effects that need to be addressed. Importantly, valid (positive) predictive biomarkers are needed for a rational use of these novel compounds. This review article presents the current state of targeted tumor therapy for the diagnostics and therapy of gastrointestinal tumors and provides assistance in integrating the current knowledge into the routine clinical context.