It is now believed that most epithelial tumors are maintained by a subpopulation of cells called cancer stem cells (CSCs) or tumor initiating cells (TICs) with stem cell-like properties, including self-renewal and multilineage differentiation capacity. Recently new insights into this population have emerged in certain epithelial tumor types, including their Claudin(low) phenotype and its importance to the epithelial-mesenchymal transition (EMT) process. Taken together, CSCs, EMT and Claudins appear to constitute an axis-of-evil in cancer, for which better understanding may lead to new therapeutic platforms.