Emerging data suggest that stem cells may be one of the key elements in normal tissue regeneration and cancer development, although they are not necessarily the same entity in both scenarios. As extensively demonstrated in the hematopoietic system, stem cell repopulation is hierarchically organized and is intrinsically limited by the intracellular cell cycle inhibitors. Their inhibitory effects appear to be highly associated with the differentiation stage in stem/progenitor pools. While this negative regulation is important for maintaining homeostasis, especially at the stem cell level under physiological cues or pathological insults, it constrains the therapeutic use of adult stem cells in vitro and restricts endogenous tissue repair after injury. On the other hand, disruption of cell cycle inhibition may contribute to the formation of the so-called 'tumor stem cells' (TSCs) that are currently hypothesized to be partially responsible for tumorigenesis and recurrence of cancer after conventional therapies. Therefore, understanding how cell cycle inhibitors control stem cells may offer new strategies not only for therapeutic manipulations of normal stem cells but also for novel therapies selectively targeting TSCs.