With the growing interest in converting a wide variety of biomass-based feedstocks to biofuels, there is a need to develop effective procedures for the design and optimization of multi-feedstock biorefineries. The unifying goal of this work is the development of systematic methodologies and procedures for designing flexible multifeedstock biorefineries. This work addresses four problems that constitute building blocks towards achieving the unifying goal of the dissertation. The first problem addresses the design and techno-economic analysis of an integrated system for the production of biodiesel from algal oil. With the sequestration of carbon dioxide from power plant flue gases, algae growth and processing has the potential to reduce greenhouse gas emissions. Algae are a non-food oil feedstock source and various pathways and technologies for obtaining algal oil were investigated. Detailed economic and sensitivity analysis reveal specific scenarios that lead to profitability of algal oil as an alternative feedstock. In the second problem, a new safety metric is introduced and utilized in process design and selection. A case study was solved to assess the potential of producing biodiesel from sewage sludge. The entire process was evaluated based on multiple criteria including cost, technology and safety. The third problem is concerned with incorporating flexibility in the design phase of the development of multi-feedstock biofuel production processes. A mathematical formulation is developed for determining the optimal flexible design for a biorefinery that is to accommodate the use of multiple feedstocks. Various objective functions may be utilized for the flexible plant depending on the purpose of the flexibility analysis and a case study is presented to demonstrate one such objective function. Finally, the development of a systematic procedure for incorporating flexibility and heat integration in the design phase of a flexible feedstock production process is introduced for the fourth problem. A mathematical formulation is developed for use in determining the heat exchange network design. By incorporating the feedstock scenarios under investigation, a mixed integer linear program is generated and a flexible heat exchange network scheme can be developed. The solution provides for a network that can accommodate the heating and cooling demands of the various scenarios while meeting minimum utility targets.