Hooper and colleagues show that the transcription factor NFIL3 integrates signals from the circadian clock to regulate T helper 17 (TH17) cell development in mice. NFIL3 suppressed TH17 cell development by repressing Rorc (which encodes RORγt) transcription, and NFIL3 itself was suppressed by the clock regulator REV-ERBα. Nfil3 and Rorc were expressed in opposite phases of the circadian cycle, with Nfil3 expression lower during the day (a 12-hour light cycle) and higher at night (a 12-hour dark cycle). Accordingly, CD4+ T cells isolated from mice during the day showed a higher propensity for differentiating into TH17 cells following in vitro polarization. Notably, mice exposed to chronic light-cycle perturbations had increased frequencies of TH17 cells in the spleen and small intestine, and were more susceptible to chemically induced colitis than mice maintained under a normal light cycle. Interestingly, Nfil3 polymorphisms, night-shift work and jet lag are all linked to human inflammatory diseases — the authors suggest that this could be due to the disruption of circadian pathways that regulate pro-inflammatory immune responses.