Covering: 1995 to 2022Tumors possess both genetic and phenotypic heterogeneity leading to the survival of subpopulations post-treatment. The term cancer stem cells (CSCs) describes a subpopulation that is resistant to many types of chemotherapy and which also possess enhanced migratory and anchorage-independent growth capabilities. These cells are enriched in residual tumor material post-treatment and can serve as the seed for future tumor re-growth, at both primary and metastatic sites. Elimination of CSCs is a key goal in enhancing cancer treatment and may be aided by application of natural products in conjunction with conventional treatments. In this review, we highlight molecular features of CSCs and discuss synthesis, structure-activity relationships, derivatization, and effects of six natural products with anti-CSC activity.