Here, we discuss the expected hallmark(s) of the cancer cell of origin and how this may be related to a new tumor cell phenotype, namely “energetic” cancer stem cells (e-CSCs). e-CSCs show many features that would be characteristic of the cancer cell of origin, including the over-expression of p21-WAF (CDKN1A), a key marker of senescence. It is tempting to speculate that the cancer cell of origin and e-CSCs are closely related entities. e-CSCs possess a hybrid phenotype, sharing key hallmarks of senescence, “stemness” and cancer. e-CSCs are hyper-proliferative and have elevated mitochondrial metabolism, with an NRF2-mediated anti-oxidant response signature, including glutaredoxin (GLRX) and ALDH3A1 over-expression, possibly related to their escape from senescence. Finally, in e-CSCs, BCAS1 (Breast carcinoma-amplified sequence-1) protein expression was up-regulated by >100-fold. BCAS1 is a candidate oncogene associated with “stemness” and aggressive oncogenic behavior, such as Tamoxifen resistance.