Currently, methane is transformed into methanol through the two-step syngas process, which requires high temperatures and centralized production. While the slightly exothermic direct partial oxidation of methane to methanol would be preferable, no such process has been established despite over a century of research. Generally, this failure has been attributed to both the high barriers required to activate methane as well as the higher activity of the CH bonds in methanol compared to those in methane. However, a precise and general quantification of the limitations of catalytic direct methane to methanol has yet to be established. Herein, we present a simple kinetic model to explain the selectivity–conversion trade-off that hampers continuous partial oxidation of methane to methanol. For the same kinetic model, we apply two distinct methods, using ab initio calculations and fitting to a large experimental database, to fully define the model parameters. We find that both methods yield strikingly similar results, namely, that the selectivity of methane to methanol in a direct, continuous process can be fully described by the methane conversion, the temperature, and a catalyst-independent difference in methane and methanol activation free energies, Δ<i>G</i><sup>a</sup>, which is dictated by the relative reactivity of the C–H bonds in methane and methanol. Stemming from this analysis, we suggest several design strategies for increasing methanol yields under the constraint of constant Δ<i>G</i><sup>a</sup>. These strategies include “collectors”, materials with strong methanol adsorption potential that can help to lower the partial pressure of methanol in the gas phase, aqueous reaction conditions, and/or diffusion-limited systems. Here, by using this simple model to successfully rationalize a representative library of experimental studies from the diverse fields of heterogeneous, homogeneous, biological, and gas-phase methane to methanol catalysis, we underscore the idea...