Ab initio methods can be used to elucidate the nature of active sites as well as the influence of the surrounding environment on catalytic kinetics. Theory can be coupled with atomic scale simulation in order to track the molecular transformations that occur over different surfaces and assess their catalytic activity and selectivity. Herein we describe the application of theory and simulation to two specific example systems, the catalytic decomposition of NO under lean conditions, and the electrocatalytic oxidation of methanol over Pt. The results for NO decomposition under lean conditions show how density functional theory calculations and kinetic Monte Carlo simulation can used to begin to tailor the metals that are used, the alloy composition, and the specific atomic arrangements at the surface in order to optimize catalytic performance. Alloying Pt with nearly 50% Au leads to turnover rates that are nearly four times larger than Pt surface alone. The specific arrangement of Pt and Au create special Pt “+-site” ensembles that reduce surface poisoning by oxygen. In the second example, we describe the elementary pathways for methanol decomposition to CO in both the vapor as well as the liquid phase. The presence of solution significantly alters the overall reaction energies by stabilizing charged complexes that form. The presence of solution drives the heterolytic activation of C–H and O–H bonds over Pt rather than the homolytic activation thus leading to the generation of protons in the aqueous media. In addition, an external potential can be applied in order to model electrochemical systems. These effects are found to be quite important in the electrochemical phase behavior of water over Pt.