Cancer stem cells werehave originally been identified in leukemia and later in several solid tumor types. They have very different properties from the bulk of the tumor, as they divide much more slowly and have very efficient drug- resistance mechanisms. Current treatments might largely spare cancer stem cells, thus leading to tumor recurrence and metastasis. The recent identification of growth and differentiation pathways responsible for cancer stem cell proliferation and survival will help in the discovery identification of novel therapeutic targets. Developing selective drugs against cancer stem cells offers great therapeutic opportunities but also provides for major challenges regarding preclinical models, therapeutic windows, and clinical study end points.