Reversible withdrawal into a quiescence cycle is an active process. (A) Schematic illustration of the quiescence cycle in context of the general cell cycle. Entry of cells into the quiescence cycle and ‘G0’ requires nutrient starvation (particularly in yeast cells) and other extrinsic cues, which both in yeast and mammalian cells might all funnel into regulating the activity of TOR, PKA and AMPK to permit induction of a quiescence program. Re-entry into the cell cycle requires nutrients and extrinsic cues. The systemic inputs required for triggering exit from proliferation, or re-entry into the cell cycle from quiescence remain poorly understood. Not all cells within a quiescent population will re-enter the cell cycle upon receiving appropriate cues and some cells appear to be uniquely adapted to re-enter the cell cycle. This program of reversible arrest includes induction of a quiescence program that involves an active suppression of alternative non-dividing fates (see B). Critical determinants of this program remain to be discovered. Nutrient-dependent commitment steps are illustrated in bold with black arrows. In proliferating populations, the decision to enter quiescence was traditionally thought to be in G1 (red arrowhead) when a cell assesses its cellular state in the context of external conditions, but recent evidence suggests that key control mechanisms might already be in place at the end of the preceding cell cycle (orange arrowhead). (B) Quiescence involves the induction of programs beyond mitotic arrest. Signatures of different phases of the quiescence cycle are illustrated. Cells entering G0 from G1 block alternate non-dividing states, such as senescence, death and differentiation. Even within such a population of non-dividing cells, there is heterogeneity in that only some cells are responsive to subsequent cues to be able to exit quiescence. To maintain the G0 state, cells induce survival pathways and nutrient uptake; they also must maintain identity and avoid precocious activation. Upon receiving an appropriate stimulus, which might include nutrient cues, the responsive cells (blue) within this population of cells will exit G0 and re-enter G1. Non-responsive cells are shown in red. Whether the heterogeneity arises from intrinsic variation in activation thresholds of key control mechanisms or temporal asynchrony of the population is not known.