Fatty acid amide hydrolase (FAAH) is a member of the amidase signature family and is responsible for the hydrolytic deactivation of fatty acid amide neuromodulators, such as anandamide. FAAH carries an unusual catalytic triad consisting of Lys-Ser-Ser, which uniquely enables the enzyme to cleave amides and esters at similar rates. The acylation of 9Z-octadecenamide (oleamide, a FAAH reference substrate) has been widely investigated by computational methods, and those have shown that conformational fluctuations of the active site affect the reaction barrier. Empirical descriptors have been devised to provide a possible mechanistic explanation for such conformational effects, but a first-principles understanding is still missing. A comparison of FAAH acylation with a reference reaction in water suggests that transition-state stabilization is crucial for catalysis because the activation energy barrier falls by 6 kcal/mol in the presence of the active site. With this in mind, we have analyzed the enzymatic reaction using the differential transition-state stabilization (DTSS) approach to determine key active-site residues for lowering the barrier. We examined several QM/MM structures at the MP2 level of theory and analyzed catalytic effects with a variation perturbation partitioning of the interaction energy into electrostatic multipole and penetration, exchange, delocalization, and correlation terms. Three residues - Thr236, Ser218, and one water molecule appear to be essential for the stabilization of the transition state, a conclusion that is also reflected by catalytic fields and agrees with site-directed mutagenesis data. An analogous analysis for URB524, URB618, and URB694 (three potent representatives of covalent, carbamate-based FAAH inhibitors) confirms the importance of the residues involved in oleamide acylation, providing insight for future inhibitor design.