The cancer stem cell model in solid tumors has evolved significantly from the early paradigm shifting work highlighting parallels between the stem cell hierarchy in hematologic malignancies and solid tumors. Putative stem cells can dedifferentiated, be induced by context, and be the result of accumulated genetic mutations. The simple hypothesis that stem cell therapies will overcome the minority of cells that lead to recurrence has evolved with it. Nevertheless, the body of evidence that this field is clinically relevant in patients and patient care has grown with the complexity of the hypotheses, and numerous clinical strategies to target these cells have been identified. Herein we review this progress and highlight the work still outstanding.