Heteroaromatic azadienes, especially 1,2,4,5-tetrazines, are extremely reactive partners with alkenes in inverse-electron-demand Diels–Alder reactions. Azadiene cycloaddition reactions are used to construct heterocycles in synthesis and are popular as bioorthogonal reactions. The origin of fast azadiene cycloaddition reactivity is classically attributed to the inverse frontier molecular orbital (FMO) interaction between the azadiene LUMO and alkene HOMO. Here, we use a combination of ab initio, density functional theory, and activation-strain model calculations to analyze physical interactions in heteroaromatic azadiene–alkene cycloaddition transition states. We find that FMO interactions do not control reactivity because, while the inverse FMO interaction becomes more stabilizing, there is a decrease in the forward FMO interaction that is offsetting. Rather, fast cycloadditions are due to a decrease in closed-shell Pauli repulsion between cycloaddition partners. The kinetic–thermodynamic relationship found for these inverse-electron-demand cycloadditions is also due to the trend in closed-shell repulsion in the cycloadducts. Cycloaddition regioselectivity, however, is the result of differences in occupied–unoccupied orbital interactions due to orbital overlap. These results provide a new predictive model and correct physical basis for heteroaromatic azadiene reactivity and regioselectivity with alkene dieneophiles.