The discovery and isolation of the hematopoietic stem cell (HSC) from bone marrow grafts introduced the concept of a cell type capable of restoring hemato-poiesis in irradiated mice. The interest in a possible “leukemia stem cell” (LSC) gave rise to multiple studies using similar techniques to detect mature leukemic cells, which shared a biomarker profile with the HSC. Interests expanded to include solid cancers and resulted in adaptations of stem cell detection methods specifically for cancer stem cells (CSCs), which are rapidly improving. Here we discuss the development of these methods, their advantages and limitations, and highlight some detection targets which are featured consistently in the literature.