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Tissue-specific stem cells (TSSCs) are a very unique cell type, with critical and well-defined roles for the homeostasis of high turnover tissues (such as the blood and the skin). Emerging evidence suggests that TSSCs are implicated in malignancies, with several theories being proposed and tested, including many attempts to identify the cells of origin and studies deigned to understand how TSSCs participate in age-related increase in cancer risk. A currently unexplored possibility in this respect is the plausible theory that an oncogenic event that arises at a TSSC would promote tissue replenishment by cells containing these mutations, with progressive propagation of such mutated TSSCs in the niche. Therefore, the effect of a somatic oncogenic event in a single TSSC may have more important implications than previously anticipated, resulting in sustained and progressively higher cancer risk. This model could have important implications for tumor recurrence, since in some cases the underlying cause might be the development of a new tumor originated from daughter cells of the TSSC that suffered the first oncogenic hit, rather than proliferation of residual cancer cells. In this review, we present and discuss approaches for testing the proposed theory of tumorigenesis and cancer risk, as well as practical implications for biomedical research and clinical practice., (Copyright © 2013 Elsevier B.V. All rights reserved.)