Many biological C‐H activation reactions exhibit nonclassical kinetic isotope effects (KIEs). These nonclassical KIEs are too large (k_H/k_D > 7) and/or exhibit unusual temperature dependence such that the Arrhenius prefactor KIEs (A_H/A_D) fall outside of the semiclassical range near unity. The focus of this minireview is to discuss such KIEs within the context of the environmentally coupled hydrogen tunneling model. Full tunneling models of hydrogen transfer assume that protein or solvent fluctuations generate a reactive configuration along the classical, heavy‐atom coordinate, from which the hydrogen transfers via nuclear tunneling. Environmentally coupled tunneling also invokes an environmental vibration (gating) that modulates the tunneling barrier, leading to a temperature‐dependent KIE. These properties directly link enzyme fluctuations to the reaction coordinate for hydrogen transfer, making a quantum …