The circadian clock interacts with other regulatory pathways to tune physiology to predictable daily changes and unexpected environmental fluctuations. However, the complexity of circadian clocks in higher organisms has prevented a clear understanding of how natural environmental conditions affect circadian clocks and their physiological outputs. Here, we dissect the interaction between circadian regulation and responses to fluctuating light in the cyanobacterium Synechococcus elongatus. We demonstrate that natural changes in light intensity substantially affect the expression of hundreds of circadian-clock-controlled genes, many of which are involved in key steps in metabolism. These changes in expression arise from control of RNA polymerase recruitment to promoters by circadian and light-responsive regulation of a network of transcription factors including RpaA and RpaB. Using phenomenological modeling constrained by our data, we reveal simple principles that underlie the small number of stereotyped responses of dusk circadian genes to changes in light.Circadian clocks allow organisms from almost all branches of life to alter physiology in anticipation of diurnal changes in the environment. Circadian clocks keep time using autonomous core oscillators which control output pathways to direct periodic changes in the mRNA levels (expression) of genes, ultimately leading to oscillations in higher order behaviors [1]. Laboratory studies of the outputs of circadian clocks have been primarily performed under constant conditions to isolate circadian regulation from environmental responses. In nature, however, organisms with circadian clocks must also cope with unexpected fluctuations in the environment. Thus a major challenge in chronobiology is to understand circadian clocks and their outputs in dynamic environments.Previous studies suggest that circadian clock output pathways interact with environmental responses to tailor physiological outputs to both the time of day and the current state of the environment. For example, sleep/wake cycles in Drosophila melanogaster and photosynthesis in Arabidopsis thaliana are controlled by both the circadian clock and environmental variables like day length or light [2,3]. Further, circadian clocks can modulate environmental responses based on the time-of-day in a process called circadian gating [4,5]. However, the complexity of higher organisms has prevented a detailed understanding of the interaction between circadian timing information and environmental responses. In contrast, the circadian clock in the cyanobacterium Synechococcus elongatus PCC7942, an obligate photoautotroph, has a simple architecture which controls gene expression oscillations ( Figure 1A) to influence metabolism and growth. S. elongatus must carefully monitor its environment, as the sunlight required for photosynthesis fluctuates on the * These authors contributed equally to this work.† Correspondence: osheae@hhmi.org minute, day, and seasonal timescales (Figure 1B,[6]). While it is well understood how the ...