Biorefineries are envisaged to produce green transportation fuels and chemicals by upgrading biomass in a sequence of processing steps. Although considerable emphasis has been given so far to the "upstream" conversion of biomass to intermediate platforms (sugars or syngas), progress in "downstream" conversion to chemicals and intermediates is still lagging. Due to the oxygen present in biomass and the diversity of raw materials derived from biomass, the necessary downstream reaction and separation processes are generally different from existing ones based on fossil fuels. Furthermore, there is limited data available on physical properties of such molecules, and on their full array of chemical transformations, and their kinetics and thermodynamics. These challenges lead to several emerging opportunities for systems and computational research, spanning several scales: elucidation of the underlying chemistry at the mechanistic level, modeling and design at the reactor and process level, and an enterprise-level analysis of process economics and environmental considerations. This talk will discuss recent results on: i) the elucidation of the chemical transformations involved in biomass conversion using RING, a recently developed reaction network generation and analysis tool, and ii) the design and optimization of novel reaction-separation processes for biomass-based chemical synthesis. It will also highlight several avenues for research in computational chemistry and chemical informatics, microkinetic and multiscale modeling, and process design, optimization and control, which can collectively have a major impact on the realization of the ambitious concept of an integrated biorefinery.