Biorefineries provide economic, environmental, and social benefits towards sustainable development. Because of the relatively small size of typical biorefineries compared to oil and gas processes, it is necessary to evaluate the options of decentralized (or distributed) plants that are constructed near the biomass resources and product markets versus centralized (or consolidated) facilities that collect biomass from different regions and distribute the products to the markets, benefiting from the economy of scale but suffering from the additional transportation costs. The problem is further compounded when, in addition to the economic factors, environmental and safety aspects are considered. This work presents an integrated approach to the design of biorefining facilities while considering the centralized and decentralized options and the economic, environmental, and safety objectives. A superstructure representation is constructed to embed the various options of interest. A mathematical programming formulation is developed to transform the problem into an optimization problem. A new correlation is developed to estimate the capital cost of biorefineries and to facilitate the inclusion of the economic functions in the optimization program without committing to the type of technology or the size of the plant. A new metric called Total Process Risk is also introduced to evaluate the relative risk of the process. Life cycle analysis is applied to evaluate environmental emissions. The environmental and safety objectives are used to establish tradeoffs with the economic objectives. A case study is solved to illustrate the value and applicability of the proposed approach.