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Jiang et al. (Research Article, 11 October 2011, DOI: 10.1126/scisignal.2002152) used a combined experimental and computational modeling approach to study the dynamic response behavior of covalent modification cycles in the presence of downstream targets (“loads”). Despite remarkable agreement between experiments and model predictions, there exists an apparent discrepancy in their approach because the utilized theoretical model does not reflect the bifunctional nature of the enzyme system used in experiments. Furthermore, a simple extension of the model to the case of bifunctional enzymes yields predictions that are partially at variance with the experimental results. It seems that an appropriate mechanistic model would have to reconcile two apparent contradictory concepts: ultrasensitivity and bifunctionality.