Cancer stem cells (CSCs), also known as tumor initiating cells or tumor repopulating cells, which comprise only a small fraction of tumor, have received tremendous attention during the past two decades, as they are considered as the ringleader for initiation and progression of tumors, therapy resistance, metastasis, and recurrence in the clinic. Hence, eradicating CSCs is critical for successful cancer treatment. To that end, various CSC-targeting therapeutic agents have been pursued. However, these CSC-specific drugs are ineffective toward bulk cancer cells. Furthermore, these anti-CSC drugs not only eradicate CSCs but also affect conventional stem cells in normal organs or tissues. By virtue of the enhanced permeability and retention (EPR) effect, nanomaterial drug delivery systems (NDDSs) passively accumulate in tumor tissues, thereby alleviating severe side effects toward normal viscera. NDDSs can be further functionalized with CSC-specific binding molecules to promote targeted drug delivery toward CSCs. Moreover, NDDSs have unique advantages in encapsulating CSC-specific drugs and cytotoxic agents, realizing synchronized killing of CSCs and bulk cancer cells both temporally and spatially. For these reasons, leveraging nanotherapeutic strategies to target CSCs has gained tremendous attention recently.Some ten years ago, we summarized five basic features of efficient nanotherapeutics (the five features principle), which consist of long circulation, tumor accumulation, deep penetration, cellular internalization, and drug release. Based on this design rationale, we constructed several NDDSs, including nanogels with adaptive hydrophobicity, CSC-derived microparticles with tailored softness, and tumor exosome sheathed porous silicon biomimetic nanoparticles, for targeted drug delivery to tumor. To our astonishment, these NDDSs that possess the five basic features achieve decent drug delivery efficiency toward not only bulk tumor cells but more importantly CSCs. Consequently, such nanotherapeutics as-designed based on the five features principle are potent in eradicating CSCs, even with only cytotoxic drugs, for instance, doxorubicin. Furthermore, commercialized nanomedicines, such as Doxil and Abraxane, can be endowed with these five basic features by hyperbaric oxygen therapy and therefore achieve outstanding drug delivery efficiency, potent CSC elimination, and efficient cancer therapy. These studies suggest that intractable CSCs can be tackled with a material-based approach, highlight the critical role of the five features principle in designing effective nanotherapeutics, and pinpoint the significance of drug delivery efficiency in eliminating CSCs and bulk cancer cells.