Several decades after the first notion that cancer cells are heterogeneous, not only histologically but also at the level of tumorigenicity, the existence of a tumor initiation population (so-called cancer stem cells) is now widely accepted. Here, we review the historical background leading up to the identification of this special cancer cell population and its role in the resistance of tumors to conventional therapies. In addition, we briefly review the clinical targeting strategy of the specific signaling network for cancer stem cells. Current clinical trials with newly developed drugs or older drugs for other uses are summarized to provide an understanding of the current status of strategies to target cancer stem cells.