Advanced tumors represent a genetically heterogeneous population of cells, which compromise subpopulations with distinct properties. Research indicates that a specific population of cells within the heterogeneous population contain stem cell-like properties. These ‘cancer stem cells’ are much like normal stem cells and have the capacity to self-renew, sustain the entire cancerous tissues and provide a reservoir of cells for recurrence after therapy and drug resistance. Cancer stem cells can arise from normal, adult stem cells, from progenitor cells or from fully matured cell types. They are likely generated by the process of epithelial-mesenchymal transition, through which differentiated cells acquire stem-cell like properties. This process potentially underlies the mechanism by which metastases evolve. Furthermore, mutations may render cancer cells dependent on the activity of one or more specific signaling pathways in the cell. This phenomenon is termed ‘oncogene addiction’ and represents the Achilles’ heel of the cancer cell. As the concept of oncogene addiction in tumor cells proves to be very complex, additional models have been proposed to account for the variations in pathway dependencies and their intricate interactions. The combined knowledge concerning cancer stem cells, oncogene addiction and drug therapy resistance may lead to the identification of new avenues to improved drug strategies that address tumor heterogeneity and mechanisms of escape.