When carbon sources are low, Escherichia coli and other bacteria enter stationary phase: they stop dividing and activate a transcriptional program to protect the cells from stress and promote long-term survival. The master regulator of this process is the sigma factor RpoS (also known as σS). Under normal conditions, RpoS is translated but is immediately degraded by the AAA+ protease ClpXP in a process dependent on the adaptor protein SprE. When cells are starved for carbon, RpoS is stabilized; conversely, upon addition of glucose (nutrient upshift), RpoS is quickly degraded. Silhavy and colleagues have now used nutrient upshifts with different carbon sources and the power of genetics to identify the molecular signals that control RpoS stability. They found that carbon metabolism is necessary to trigger RpoS degradation. Furthermore, functional glycolysis or the TCA cycle is required, pointing to the energy-transducing molecules produced by these pathways: ATP and NADH. To determine which molecule is involved, the authors used carbonyl cyanide m-chlorophenylhydrazone (CCCP) to disrupt the proton motive force, thereby blocking oxidative phosphorylation. When succinate was provided as a carbon source, the CCCP-treated cells could not produce ATP from glycolysis or from oxidative phosphorylation, and RpoS was not degraded. Importantly, ClpXP was still active under those conditions. These results indicate that RpoS degradation is sensitive to ATP levels. This conclusion was further supported by data under conditions in which ATP biosynthesis was defective. Finally, the authors reconstituted the system in vitro, using purified RpoS, SprE and ClpXP, and observed RpoS stabilization under low ATP levels. Interestingly, another ClpXP substrate tested did not show a similar sensitivity to ATP concentrations. Exactly how ATP controls RpoS proteolysis by ClpXP will likely be revealed in future biochemical and structural work. (Genes Dev. 26, 548–553, 2012)