274 275The emergence of innovative chemistry informatics (cheminformatics) is threatening the sustainability of bioethanol production from palm oil empty fruit bunch (EFB) in Indonesia. With the friendliness and convenience offered by cheminformatics, many bioethanol production processes nowadays prefer to determining optimum condition and forecasting the results computationally through response surface methodology (RSM). RSM is one of cheminformatics (called by RSM-CI; Response Surface Methodology—Chemistry Informatics) that explores the relationships between several explanatory variables and one or more response variables. Indonesia had established bioethanol production pilot plant by using fully automatic computerized system supported by sufficient ICT emerging technology and database. Bioethanol production from cellulose-based material is one of the popular bioprocess engineering research fields in Indonesia in the last five years, since palm plantation biomass waste became the most concern potency for bioethanol raw material since Indonesia is the world leading producer in palm oil. The purpose of this chapter is to assess the impact of RSM as a practical cheminformatics to support bioprocess technology; bioethanol technology processes by optimizing the operations’ variables and easily adopted in automatic computerized system ICT emerging technology.