Cancer stem cell is a progressive concept moving forward to interpret the hard-to-cure nature of cancer and the relevant behavior in response to clinical therapies. Despite the remaining debates regarding the existence of cancer stem cells, the cancer stem cell model provides a potential approach for advanced innovative therapies targeting the roots of cancer, which has enhanced treatment outcomes. This chapter summarizes advanced perspectives in the field of cancer stem cell research, including experimental strategies for targeting these cells, highlights challenges of this theory, and explores feasible therapeutic strategies for overcoming the intrinsic resistance of cancer stem cells to clinical treatment.