This article describes the key challenges and opportunities in modeling and optimization of biomass-to-bioenergy supply chains. It reviews the major energy pathways from terrestrial and aquatic biomass to bioenergy/biofuel products as well as power and heat with an emphasis on "drop-in" liquid hydrocarbon fuels. Key components of the bioenergy supply chains are then presented, along with a comprehensive overview and classification of the existing contributions on biofuel/bioenergy supply chain optimization.