According to the cancer progression model, several events are required for the progression from normal epithelium to carcinoma. Due to their extended life span, stem cells would represent the most likely target for the accumulation of these genetic events but this has not been formally proven for most of solid cancers. Even more importantly, cancer stem cells seem to harbor mechanisms protecting them from standard cytotoxic therapy. While cancer stem cells have been demonstrated to be responsible for therapy resistance in glioblastoma and pancreatic cancer, further evidence now points to similar mechanisms in colon cancer stem cells. Therefore, it appears reasonable to conclude that there is sufficient evidence now for the existence of cancer stem cells in several epithelial tumors and that these cancer stem cells pose a significant threat via their resistance to standard therapies. Accumulating evidence suggests, however, that novel approaches targeting cancer stem cells are capable of overcoming these resistance mechanisms. To further foster our understanding of in vivo cancer stem cell biology, novel imaging modalities in conjunction with clinically most relevant cancer stem cell models need to be developed and utilized. These studies will then pave the way to better elucidate the underlying regulatory mechanisms of cancer stem cells and develop platforms for targeted theragnostics, which may eventually help improving the prognosis of our patients suffering from these deadly diseases.