The morphology of several tumors mimics developmentally early tissues, and tumors often express early developmental markers characteristic of the germ line lineage. The presence of these markers in neoplastic cells could reflect the dedifferentiation of somatic cells in which cancer develops or cancer origination in primitive stem cells closely related to the epiblast/germ line. The identification of primitive germ line-derived very small embryonic/epiblast-like stem cells, which are deposited early in embryogenesis in developing organs and persist in several organs into adulthood, raised the possibility that cancer may originate in these cells. In this review, we hypothesize that very small embryonic/epiblast-like stem cells could be a missing link that support the more than 100-year-old concepts of the embryonic rest or germ line origin hypotheses of cancer development; however, further experimental evidence is needed to support this hypothesis.