Density functional theory and ab initio calculations indicate that nucleophiles can significantly reduce enthalpic barriers to methane C-H bond activation. Valence bond analysis suggests the formation of a two-center three-electron bond as the origin for the catalytic nucleophile effect. A predictive model for methane activation catalysis follows, which suggests that strongly electron-attracting and electron-rich radicals, together with both a negatively charged and strongly electron-donating outer sphere nucleophile, result in the lowest reaction barriers. It is corroborated by the sensitivity of the calculated C-H activation barriers to the external nucleophile and to continuum solvent polarity. More generally, from the present studies, one may propose proteins with hydrophobic active sites, available strong nucleophiles, and hydrogen bond donors as attractive targets for engineering novel methane functionalizing enzymes.