The circadian clock orchestrates 24-h rhythms in physiology in most living organisms. At the molecular level, the dogma is that circadian oscillations are based on a negative transcriptional feedback loop. Recent studies found the NAD⁺-dependent histone deacetylase, SIRT1, directly regulates acetylation status of clock components and influences circadian amplitude in cells. While Nakahata et al. [Nakahata Y, Kaluzova M (2008) Cell 134:329–340] reported that loss of SIRT1 increases amplitude through BMAL1 acetylation, Asher et al. [Asher G, Gatfield D (2008) Cell 134:317–328] reported that loss of SIRT1 decreases amplitude through an increase in acetylated PER2. To address this SIRT1 paradox, we developed a circadian enzymatic model. Predictions from this model and experimental validation strongly align with the findings of Asher et al., with PER2 as the primary target of SIRT1. Further, the model suggested SIRT1 influences BMAL1 expression through actions on PGC1α. We validated this finding experimentally. Thus, our computational and experimental approaches suggest SIRT1 positively regulates clock function through actions on PER2 and PGC1α.