Two opposing hypotheses of the origin of cancer have existed for many decades. One hypothesis postulates that the adult stem cell is needed to initiate the carcinogenic process, whereas the other claims a somatic differentiated cell can dedifferentiate or be reprogrammed to regain properties associated with cancer cells. Recent reemergence of the cancer stem cell hypothesis and the isolation of presumptive cancer stem cells from many types of cancer have forced a reexamination of these 2 hypotheses of the origin of cancer. In addition, normal embryonic and adult stem cells have now been isolated and partially characterized. Furthermore, the demonstration of embryonic-like stem cells, being isolated from adult-differentiated skin fibroblast cells of mice, monkey, and human beings, provides a newer opportunity to determine which of these 2 hypotheses might explain the cell type for initiating the carcinogenic process. The goal of this review is to integrate these recent findings, concerning the isolation of normal and cancer stem cells, with several of the classical concepts of carcinogenesis (initiation/promotion/progression; mutation/epigenetic; stem cell theory/dedifferentiation hypotheses; oncogene-tumor suppressor theory). Although the weight of the evidence in this review seems to support the stem cell hypothesis, only future studies, probably using comparative animal and human oncologic studies, will determine if targeting the cancer stem cell, with individualized medical approaches, will improve cancer prevention and therapy.