Recent research on embryonic and adult stem cells questions the currently accepted models of multi-step carcinogenesis in solid cancer. Accordingly, differentiated epithelial cells are considered to be the main target for mutational steps, leading to a growth and survival advantage of malignantly transformed cells. In contrast, the stem cell model of carcinogenesis emphasizes the role of stem cells as the initiating structure for tumor development. Yet, it is unclear if tumors contain dysregulated (embryonic) stem cells or if tumors consist of differentiated adult cells that obtained a de-differentiated stem cell-like phenotype. Here, we review the current knowledge on the roles of stem cells in gastrointestinal cancer formation and the implication on future diagnostic and therapeutic strategies.