The oxidation of substrates via the cleavage of thermodynamically strong C–H bonds is an essential part of mammalian metabolism. These reactions are predominantly carried out by enzymes that produce high valent metal–oxido species, which are directly responsible for cleaving the C–H bonds. While much is known about the identity of these transient intermediates, the mechanistic factors that enable metal–oxido species to accomplish such difficult transformations are still incomplete. For synthetic metal–oxido species, C–H bond cleavage is often mechanistically described as synchronous proton coupled electron transfer (PCET). However, data have emerged that suggest the basicity of the M– oxido unit is the key determinant in achieving enzymatic function, thus requiring alternative mechanisms whereby proton transfer (PT) has a more dominate role than electron transfer (ET). This presentation will describe our research to gain mechanistic insights into how metal–oxido complexes activate C–H bonds. We have used a series of well-characterized Mn(III)– and M(IV)–oxido complexes to show that PT has a dominate role in the activation processes. Our experimental findings led to a proposed PCET mechanism with asynchronous transition states that is dominated by PT. To support this premise, a new semi-empirical free energy analysis was developed that can predict the relative contributions of PT and ET for a given set of substrates. These findings underscore why the basicity of M–oxido units needs to be considered in C–H functionalization.