Process simulation is a valuable tool to increase the profitability of corn-to-ethanol processes by reducing costs, increasing yield, and improving product quality. Although process simulations have been heavily used in the chemical process industries for several decades, the biofuel manufacturing industry has only begun to take advantage of this technology during the past five to ten years. Recently, the development of a corn-to-ethanol process model by the Department of Chemical Engineering at Washington University in St. Louis, using an Excel-based model and Hysys, has made it possible to simulate corn-to-ethanol processes in a simple and straightforward manner. In this discussion, we will study key assumptions to validate mass balances and examine technical challenges that must be overcome to develop a Hysys simulation of important sections in corn-to-ethanol process, such as cooking/liquefaction, distillation and evaporation. Several case studies will be presented. Finally, we will review how a rigorous process model can be leveraged to support additional business needs including stream properties estimation and process scale-up.