Oncogene research over the last century has been one of the major advances in understanding the molecular biology of malignant disease. Oncogenes are a structurally and functionally heterogeneous group of genes, whose protein products act pleiotropically and affect multiple complex regulatory cascades within the cell. They regulate cell proliferation, growth, and differentiation, as well as control of the cell cycle and apoptosis. The products of oncogenes include growth factors, growth factor receptors, signal transducers, transcription factors, and apoptosis regulators, as well as chromatin remodelers. Several distinct mechanisms have been described for the conversion of proto-oncogenes to active oncogenes. Quantitative forms of oncogene activation include multiplication (gene amplification) or translocation to an active chromatin domain that brings a growth-regulatory gene under the control of a different promoter, causing inappropriate expression of the gene. Qualitative forms include either point mutations or the production of a novel product from a chimeric gene. Further understanding of the molecular mechanisms by which oncogenes regulate normal development and tumorigenesis may lead to novel concepts in the diagnosis and treatment of cancer in humans. In this review, we focus on the role of selected oncogenes in gastrointestinal cancer.