Calcium sulfate is typically added to cement clinker to prevent flash set and to improve early age strength development without causing additional volume instabilities. Recent changes to ASTM C150, “Standard Specification for Portland Cement,” have enabled greater flexibility in determining optimum sulfate levels in Portland cement by not requiring ASTM C563, “Approximation of Optimum SO3 in Hydraulic Cement Using Compressive Strength,” to set sulfate target levels. ASTM C563 requires strength testing using only hydraulic cement at 23°C, which is not always indicative of the optimum sulfate level for field use, because supplementary materials (e.g., fly ash) might be used and the optimum sulfate level might be sensitive to temperature changes. Adding additional sulfate to account for the sulfate demand of fly ashes can enable an improvement in the early age strength for cement–fly ash systems and decrease the number of problems that may be attributed to cement–admixture–fly ash incompatibility, such as abnormal setting and strength gain. This research provides experimental data on the strength development and heat release during early hydration for cement–fly ash systems with different sulfate levels. It is demonstrated that some fly ashes have their own sulfate demand, and when these ashes are used in cement–fly ash blends there is effectively an increase in the optimal sulfate level that should be used for the Portland cement. It is also shown that the optimum sulfate level determined according to the heat of hydration measured with isothermal calorimetry is similar to the optimum sulfate level determined based on compressive strength at 1 day.