The atomistic change of C( sp3)-H to C( sp3)-O can have a profound impact on the physical and biological properties of small molecules. Traditionally, chemical synthesis has relied on pre-existing functionality to install new functionality, and directed approaches to C-H oxidation are an extension of this logic. The impact of developing undirected C-H oxidation reactions with controlled site-selectivity is that scientists gain the ability to diversify complex structures at sites remote from existing functionality, without having to carry out individual de novo syntheses. This Perspective offers a historical view of why, as recently as 2007, it was thought that the differences between aliphatic C-H bonds of the same bond type (for example, 2° aliphatic) were not large enough to distinguish them preparatively with small-molecule catalysis in the absence of directing groups or molecular recognition elements. We give an account of the discovery of Fe(PDP)-catalyzed non-directed aliphatic C-H hydroxylations and how the electronic, steric, and stereoelectronic rules for predicting site-selectivity that emerged have affected a shift in how the chemical community views the reactivity among these bonds. The discovery that site-selectivity could be altered by tuning the catalyst [i.e., Fe(CF3-PDP)] with no changes to the substrate or reaction now gives scientists the ability to exert control on the site of oxidation on a range of functionally and topologically diverse compounds. Collectively, these findings have made possible the emerging area of late-stage C-H functionalizations for streamlining synthesis and derivatizing complex molecules.