An optimization-based process synthesis framework is proposed for the thermochemical conversion of biomass and natural gas to liquid fuels (BGTL). Hydrocarbons are produced from synthesis gas either directly via Fischer-Tropsch synthesis or indirectly via catalytic conversion of methanol over ZSM-5. Different conversion technologies are investigated to examine their economic effects on BGTL refineries that produce gasoline, diesel, and kerosene. The process synthesis framework includes simultaneous heat, power, and water integration and utilizes a rigorous deterministic global optimization strategy to mathematically guarantee the minimal cost of the BGTL refineries. The refineries have at least 50% less life-cycle CO2 emissions than a standard petroleum-based refinery. Forty-eight case studies are presented to determine the effect of refinery capacity, liquid fuel composition, and biomass feedstock on the overall cost, topological design, material/energy balances, and life-cycle greenhouse gas emissions. Results suggest that these systems can be economically competitive with petroleum-based processes while achieving the 50% emissions reduction.