Standard protocols for the diagnosis of neoplasms in the gastrointestinal tract are based on histopathologic analysis in combination with clinical information. With the completion of the Human Genome Project in 2003, our understanding of the contribution of genetics to human disease has increased exponentially. This knowledge is gradually being incorporated into clinical decision-making. However, the rate at which molecular biomarkers are validated for use in mainstream clinical applications has lagged far behind that of biomarker discovery. Nevertheless, a number of molecular biomarkers are available for use in the diagnosis and management of gastrointestinal tract neoplasms. This article reviews the most common molecular biomarkers currently available for neoplasms of the luminal gastrointestinal tract and pancreas. In neoplasms of the esophagus, for which no biomarkers are currently used in routine clinical practice, those that have shown the most promise in early clinical validation studies are discussed.