Malignancies of the gastrointestinal tract are among the most common human cancers. The distinct tissues of origin give rise to a diverse set of diseases, such as colorectal cancer, pancreatic carcinoma and gastric cancers, with each associating with specific clinical features. Genomic and transcriptomic analyses have further defined the heterogeneity that occurs within these cancers by identifying so-called molecular subtypes. These subtypes are characterized by specific genetic aberrations and expression signatures that suggest important biological differences. Although at first sight this subdivision of organ-specific cancers might increase the complexity of classification, closer analysis suggests that the subtypes detected in the various malignancies are recurring. For example, nearly all gastrointestinal cancers appear to present with subtypes that are either characterized by a mesenchymal gene expression signatures, extensive immune infiltration or metabolic dysregulation. Additionally, in each of the gastrointestinal malignancies, a ‘canonical’ subtype is recognized that retains characteristic features of the epithelial tissue of origin. These common themes can enhance our collective understanding of these malignancies, and could perhaps be therapeutically exploited. In this Review, the identification of subtypes in the various gastrointestinal cancer types are discussed along with how they could be incorporated into clinical practice.