Integrating diverse energy sources to produce cost-competitive fuels requires efficient resource management. An optimization framework is proposed for a nationwide energy supply chain network using hybrid coal, biomass, and natural gas to liquids (CBGTL) facilities, which are individually optimized with simultaneous heat, power, and water integration using 162 distinct combinations of feedstock types, capacities, and carbon conversion levels. The model integrates the upstream and downstream operations of the facilities, incorporating the delivery of feedstocks, fuel products, electricity supply, water, and CO2 sequestration, with their geographical distributions. Quantitative economic trade-offs are established between supply chain configurations that (a) replace petroleum-based fuels by 100%, 75%, and 50% and (b) utilize the current energy infrastructures. Results suggest that cost-competitive fuels for the US transportation sector can be produced using domestically available coal, natural gas, and sustainably harvested biomass via an optimal network of CBGTL plants with significant GHG emissions reduction from petroleum-based processes. (C) 2012 American Institute of Chemical Engineers AIChE J, 2012