Contemporary SC Theory indicates that SCs are organised as hierarchies and that the apex SC at the top of the hierarchy can become quiescent [
44,
47]. As quiescent cells reside outside the cell cycle they are broadly insusceptible to conventional therapies, which target the mitotic mechanisms of rapidly-dividing cells [
48]. As such, ‘Quiescence’ is the first CSC therapy-resistance property. In more recent years, the description of two further mechanisms, DNA-monitoring and DNA repair during quiescence, offers further possibilities for the complexity of CSC therapy-resistance. In the first set of studies it has been shown that, rather than simply being inactive, quiescent SCs actively monitor DNA damage [
49]. The strongest evidence for this mechanism is the demonstration that loss of key cell cycle regulators such as p53, p21, p57 or the Retinoblastoma protein impairs quiescence [
50‐
53]. In addition, two related but separate studies have indicated that quiescent SCs are primed for re-entry in to the cycle in a process that involves DNA repair. Specifically, SCs have been shown to transition from G
0 to G
1 of the cell cycle via a ‘G
ALERT’ state that is primed for rapid cell cycle re-entry in response to stress [
54]. Complementing this study, it has recently been shown that quiescent HSCs can accumulate DNA damage and that many of these damaged HSCs are repaired during cell cycle re-entry rather than being signalled to undergo apoptosis [
55]. These studies suggest that the quiescent CSC may possess a collection of DNA repair mechanisms that offer protection against therapeutic intervention. Despite the difficulty associated with modelling non-dividing cells, there are indications that quiescent stem-like populations contribute to at least some tumours. For example, in primary ovarian tumours it was demonstrated that CD24
+ CSCs were slower proliferating but more tumourigenic than bulk cells, suggesting a quiescent, tumourigenic CSC population [
56]. In addition, quiescent CSCs that survive chemotherapy can re-enter the cell cycle and re-establish the tumour [
44,
57,
58].