The mechanism of N-demethylation of N,N-dimethylanilines (DMAs) by cytochrome P450, a highly debated topic in mechanistic bioinorganic chemistry (Karki, S. B.; Dinnocenczo, J. P.; Jones, J. P.; Korzekwa, K. R. J. Am. Chem. Soc. 1995, 117, 3657), is studied here using DFT calculations of the reactions of the active species of the enzyme, Compound I (Cpd I), with four para-(H, Cl, CN, NO2) substituted DMAs. The calculations resolve mechanistic controversies, offer a consistent mechanistic view, and reveal the following features: (a) the reaction pathways involve C-H hydroxylation by Cpd I followed by a nonenzymatic carbinolamine decomposition. (b) C-H hydroxylation is initiated by a hydrogen atom transfer (HAT) step that possesses a "polar" character. As such, the HAT energy barriers correlate with the energy level of the HOMO of the DMAs. (c) The series exhibits a switch from spin-selective reactivity for DMA and p-Cl-DMA to two-state reactivity, with low- and high-spin states, for p-CN-DMA and p-NO2-DMA. (d) The computed kinetic isotope effect profiles (KIEPs) for these scenarios match the experimentally determined KIEPs. Theory further shows that the KIEs and TS structures vary in a manner predicted by the Melander-Westheimer postulate: as the substituent becomes more electron withdrawing, the TS is shifted to a later position along the H-transfer coordinate and the corresponding KIEs increases. (e) The generated carbinolaniline can readily dissociate from the heme and decomposes in a nonenzymatic environment, which involves water assisted proton shift.