This letter to the editor highlights the important aspects of cancer stem cells and provides a deeper insight into the origin and characterization of these cells as well as the mechanisms contributing to drug resistance and relapse. The two currently available models (CSC and the clonal evolution model) need not be mutually exclusive to explain the origin of CSCs. The identification of CSCs (based on surface markers, drug efflux, enzyme activity, and signal transduction molecules and proteins involved in EMT processes) can help in discriminating these cells from other cell types. Moreover, CSCs prefer a hypoxic environment. This microenvironmental cue can trigger certain metabolic alterations that can orchestrate a rewiring of the epigenome. Consequently, changes in transcription factors and signaling molecules can contribute to the plasticity/inter-convertibility of the CSCs and non-CSC cellular states. Hence, an improved understanding of the mechanisms involved also provides opportunities for pharmacological manipulations. This letter also underscores the presence of precancerous stem cells as well as very small embryonic-like stem cells (VSELs) (both considered to be precursors of CSCs). These reports warrant a thorough reanalysis of the source of CSCs (lineage tracing studies), subsequent to the development of better targeted intervention approaches. © TÜBİTAK.