Tissue-specific stem cells are responsible for the maintenance of the epithelium throughout the gastrointestinal tract. The accumulation of mutations in these stem cells is the likely cause of most gastrointestinal cancers. Clonal analysis of these stem cell populations has revealed how normal homeostatic processes work and how neoplastic growth occurs. In this review, we consider the clonal dynamics of stem cells in the gastrointestinal tract. We focus on mechanisms of clonal expansion, and discuss the novel methods that have been developed to study these processes in humans. Particular consideration is given to the role of clonal analysis in understanding dysplasia and neoplasia. We consider how improvements in sequencing technology may shape future research and clinical practice.