Multiple theories exist to explain cancer initiation, although a consensus on this is crucial for developing effective therapies. 'Somatic mutation theory' suggests that mutations in somatic cells during DNA repair initiates cancer but this concept has several attached paradoxes. Research efforts to identify quiescent cancer stem cells (CSCs) that survive therapy and result in metastasis and recurrence have remained futile. In solid cancers, CSCs are suggested to appear during epithelial-mesenchymal transition by the dedifferentiation and reprogramming of epithelial cells. Pluripotent and quiescent very small embryonic-like stem cells (VSELs) exist in multiple tissues but remain elusive owing to their small size and scarce nature. VSELs are developmentally connected to primordial germ cells, undergo rare, asymmetrical cell divisions and are responsible for the regular turnover of cells to maintain tissue homeostasis throughout life. VSELs are directly vulnerable to extrinsic endocrine insults because they express gonadal and gonadotropin hormone receptors. VSELs undergo epigenetic changes due to endocrine insults and transform into CSCs. CSCs exhibit genomic instability and develop mutations due to errors during DNA replication while undergoing excessive proliferation and clonal expansion to form spheroids. Thus tissue-resident VSELs offer a connection between extrinsic insults and variations in cancer incidence reported in various body tissues. To conclude, cancer is indeed a stem cell disease with mutations occurring as a consequence. In addition to immunotherapy, targeting mutations, and Lgr5 + organoids for developing new therapeutics, targeting CSCs (epigenetically altered VSELs) by improving their niche and epigenetic status could serve as a promising strategy to treat cancer.