Publisher Summary This chapter describes a new methodology used in the estimation of the thermodynamic properties of asphaltenes. This methodology combines computer assisted structure elucidation (CASE) with atomistic simulations. To illustrate this new approach, quantitative and qualitative structural data is used as an input to a CASE program (SIGNATURE) to generate a sample of ten model asphaltene structures for a Saudi crude oil (Arab Beni). Molecular mechanics (MM) calculations and molecular dynamics (MD) simulations to estimate selected volumetric and thermal properties of the model structures are also carried out. The estimated values are in good agreement with the available experimental data. The results of this study suggest that CASE can be combined with atomistic simulations to obtain adequate estimates of the thermodynamic properties of petroleum geomacromolecules such as asphaltenes. The precipitation of asphaltene aggregates can cause problems as reservoir plugging and wettability reversal. The adsorption of asphaltene aggregates at oilwater interfaces has been shown to cause the steric stabilization of (W/O) petroleum emulsions.