Tissue turnover is a regular feature of higher eukaryotes, either as part of normal wear and tear (homeostasis) or in response to injury (regeneration). Cell replacement is achieved either through replication of existing cells or differentiation from a self-renewing pool of stem cells. The major distinction regards cellular potential, because stem cells by definition have a capacity to differentiate, while replication implies that cells adopt a single fate under physiologic conditions. A hybrid model, the facultative stem cell (FSC) model, posits that tissues contain cells that normally exhibit unipotency but have the capacity to function as stem cells upon injury. The FSC paradigm is well established in urodele amphibians, but the nature and role of FSCs in mammals is less defined. Here, we review the evidence for FSCs in two mammalian organs, the liver and the pancreas, and discuss alternative models that could account for regeneration in these organs. Developmental Dynamics 240:521–529, 2011. © 2011 Wiley-Liss, Inc.