Overcoming resistance to standard anticancer treatments represents a significant challenge. The interest regarding cancer stem cells, a cellular population that has the ability to self-renew and to propagate the tumor, was prompted by experimental evidence delineating the molecular mechanisms that are selectively activated in this cellular subset in order to survive chemotherapy. This has also stimulated combination strategies aimed at rendering cancer stem cells vulnerable to anticancer agents. Moreover, cancer stem cells offer a unique opportunity for modeling human cancers in mice, thus emerging as a powerful tool for testing novel drugs and combinations in a simulation of human disease. These novel animal models may lay the foundation for a new generation of clinical trials aimed at anticipating the benefit to patients of anticancer therapies.