Among the frontier challenges in chemistry in the 21st century are the interconnected goals of increasing control of chemical reactivity while synthesizing and diversifying complex molecules with higher efficiency. Traditional organic methods for installing oxidized functionality rely heavily on sequential acid-base reactions that require extensive functional group manipulations (FGMs). In contrast, nature routinely uses allylic and aliphatic C-H oxidation methods, generally mediated by heme and non-heme iron monooxygenase enzymes, to directly install oxidized functionality into preformed frameworks of complex molecules. Due to their ubiquity in complex molecules and inertness to most organic transformations, C-H bonds have typically been ignored in the context of methods development for total synthesis. The exceptions to this rely on substrate directing groups to facilitate site-selectivity and reactivity. The discovery and development of catalysts for the direct installation of oxygen, nitrogen and carbon into allylic and aliphatic C-H bonds are discussed. Unlike Nature which uses elaborate shape or functional group recognition active sites, these small molecule catalysts utilize differential sensitivity to the C-H bond electronics, sterics, and stereoelectronic environment to achieve predictable site-selective and -divergent oxidations in complex molecule settings- and without the requirement for directing groups. Using these catalysts a code for site-selective C-H reactivity has been delineation that has proven to be highly general across a range of C-H oxidation catalysts and reactions. Our current understanding of these interactions and the development of a catalyst reactivity model that calculates and even predicts the major site of oxidation as well as the magnitude and direction of the site-selectivity in complex substrates as a function of catalyst will be described.