Frontier Molecular Orbital (FMO) theory has long been used to describe the reactivity of Diels-Alder reactions. Although it provides a simple and powerful model to understand reactivity, it struggles to explain certain aspects of bioorthogonal Diels–Alder reactions involving 1,2,4,5-tetrazines. These reactions hold significant promise in the fields of chemical biology, medical therapy, and diagnostics. We explore the cases where FMO theory falls short in predicting the reactivity and selectivity of these bioorthogonal reactions. We present alternative models and tools that provide a more comprehensive understanding of the underlying mechanisms, ultimately contributing to the development of improved chemical tools for medical applications. We showcase the high reactivity of 2-pyridyl-1,2,4,5-tetrazines, which can be attributed to reduced distortion energy during the reaction, enabling the development of highly reactive yet stable tetrazines. We also examine the elevated reactivity of mono-substituted tetrazines, resulting from an asynchronous transition state. Lastly, we investigate dienophile reactivity, which displays non-FMO behavior based on orbital overlap.