In this article, molecular modeling of process streams and processes is combined with overall refinery optimization to select feedstocks and products, optimize the operation of different processes, and determine the most economic modifications. The molecular compositions of the hydrocarbon mixture are described using a MTHS (Molecular Type Homologous Series) matrix. To model reaction processes, structure-reactivity correlations are developed by regressing a wide range of pilot plant and commercial data. Molecular level kinetics is combined with current reactor modeling techniques. To integrate molecular modeling with plant-wide optimization, the interface between molecular compositions and bulk properties is also developed. The plant-wide optimization consists of a two-level optimization procedure, namely the site level and process level. The site level optimization addresses the overall trade-offs among the selections of feedstocks, products, processes, and the use of utilities. The process level optimization optimizes the individual processes by adjusting the detailed operating parameters. With the detailed molecular information available from the molecular model, it is possible to distinguish the contributions from different feedstocks and optimize the operation conditions to produce the most desirable products. A feedback mechanism is built for the coordination between these two levels. By optimizing the overall plant using molecular models, overall profit will be maximized by maximizing desired molecules to form valuable products, minimizing undesired ones, and routing all the molecules to their most appropriate destinations.