The cancer stem cell (CSC) hypothesis has had a major effect on the fields of cancer cell biology and clinical oncology. CSCs were originally described in hematologic malignancies, and subsequently in a variety of solid tumors. Their unique biological characteristics, including self-renewal capability, stem cell signaling pathways, relative quiescence and resistance to standard chemotherapy and radiotherapy are providing researchers and clinicians with new challenges. One important outcome of this new perspective on tumors is the recognition that effective treatment approaches will need to target both the rapidly proliferating bulk tumor cells, and the quiescent CSCs, which contain the ability to reestablish the malignancy when treatment is withdrawn. The clinical laboratory will undoubtedly see an influx of new molecular and histopathological tests to augment initial diagnosis, treatment decisions, and prognostic monitoring of cancer patients related to identifying and quantifying these as CSCs.