One of the greatest challenges of cancer therapy is not the effective elimination of the bulk of the tumor, but instead the small population of stem cells from which the tumor originated. These cells are hardy and possess the capacity for quiescence and self-renewal. More so, these cells are capable of producing the malignant progenitor cells and eventually recreate the original disease. The tumor can recruit and manipulate nonmalignant stromal and immune cells to create a protective niche where cancer stem cells can survive initial therapy and persist as minimal residual disease. New therapeutic approaches will have to overcome the microenvironmental factors that limit the impact of chemotherapy on tumor stem cells in order to eliminate minimal residual disease and provide cure in patients with cancer.