As for all stem cells, oncogenically transformed cancer stem cells (CSCs) are defined by their ability for self-renewal and multipotency. The CSC hypothesis states that, although CSCs represent a rare population of cells within a tumor, their high tumorigenic capacity drives tumorigenesis. Due to their intrinsic stem cell-like properties, CSC proliferation generates more CSCs, and all the differentiated cell types that compose the bulk of the tumor. Non-CSCs in the tumor have been shown to proliferate at a faster rate than CSCs, but have little tumor-initiating potential. Because CSCs exhibit increased resistance to toxic and chemical insults, this specific subpopulation of cells is believed to underlie resistance to chemotherapy and disease relapse. In fact, the CSC model posits that all CSCs must be eradicated to eliminate a tumor and prevent its recurrence. The cancer stem cell hypothesis has been used to explain many cancer complications resulting in poor patient outcomes including induced drug resistance, metastases to distant organs, and tumor recurrence. While the validity of the cancer stem cell model continues to be the cause of much scientific debate, a number of putative cancer stem cell markers have been identified making studies concerning the targeting of cancer stem cells possible. In this review, a number of identifying properties of cancer stem cells have been outlined including properties contributing to the drug resistance and metastatic potential commonly observed in supposed cancer stem cells. Due to cancer stem cells’ numerous survival mechanisms, the diversity of cancer stem cell markers between cancer types and tissues, and the prevalence of cancer stem cell markers among healthy stem and somatic cells, it is likely that currently utilized treatments will continue to fail to eradicate cancer stem cells. The successful treatment of cancer stem cells will rely upon the development of anti-neoplastic drugs capable of influencing many cellular mechanisms simultaneously in order to prevent the survival of this evasive subpopulation. Natural compounds represent a historically rich source of novel, biologically active compounds which are able to interact with a large number of cellular targets while limiting the painful side-effects commonly associated with cancer treatment. A brief review of select natural products that have been demonstrated to diminish the clinically devastating properties of cancer stem cells or to induce cancer stem cell death is also presented.