In this work, we present a process systems engineering framework that allows the integration of catalysis, process synthesis, and fuel property modelling enabling the systematic design of fuels with tailored properties and the biorefineries able to produce them. Methodologically, the proposed framework relies on a superstructure-based formulation in which three hierarchical decisions are made: what chemical products will undergo chemical transformations? what chemistries will be used to transform these chemical products? and which specific catalyst and processes will be used? This optimization framework is coupled with a fuel property model such that the decisions made at the process synthesis level are constrained by the desired fuel properties. We apply this framework to the problem of ethanol upgrading with an emphasis on three specific problems: First, we show how we can design biorefineries for the production of fuels (gasoline, diesel, or jet fuel) with specific properties. Second, we study the interplay between fuel properties and profit, and we show how the constraints imposed on the fuel properties impact both the optimal biorefinery designed and its economics. Finally, we show how the studied framework can be used to find the optimal biorefinery associated with a specific chemistry or catalyst. The results presented constitute the first systematic and comprehensive study of ethanol upgrading in which the simultaneous process and product design are considered.