Targeting and killing specific cells discriminately has been the goal of targeted therapy dating back to the era of Paul Ehrlich. The discovery of cancer stem cells has caused a paradigm shift within the cancer field and provided an opportunity to use targeted therapies such as targeted toxins to bind and kill these cells selectively. A number of targeted toxins have been developed against recently identified cancer stem cell markers. In this review we discuss the development and current status of these exciting novel drugs and their potential use to combat drug-refractory relapse.