Cancers of the upper gastrointestinal tract and pancreas are still among the most devastating neoplastic diseases. Cure is achieved only if the diagnosis is made at an early stage. Given the low incidence of these neoplasias in the Western world, surveillance programs are not available and practicable; therefore, most of the patients suffering from these cancers are diagnosed in a locally advanced or metastatic stage and treated in a palliative setting. Treatment response and duration is crucial and maintenance strategies are therefore desperately warranted. Molecular targeted therapies with a low toxicity profile could make ideal proponents for this attempt. This short review summarizes the relevant trials investigating maintenance treatments in esophageal cancer, gastric cancer and pancreatic cancer.