The paper outlines a systems approach with capabilities to address common complexities and practicalities in the design of real-life integrated biorefineries. The approach favors a decomposition of the problem into process synthesis, process integration and flowsheeting. The synthesis of paths introduces a graph representation sufficiently generic to model the general problem. Likewise, the development of product portfolios offers a generic cascade representation that combines thermodynamics with mathematical programming. The methodology renders high-throughput capacity and has been exploited to review large combinations of paths through exhaustive screening, subsequently leading to significant savings in capital and operating costs. The paper highlights results from the approach as it has configured the operation and the evolution of existing pilots and demos. The methodology is being extended to address strategic decisions and the better integration of the biorefinery concept. The paper explains limitations and opportunities of existing methods and tools, highlighting the scope for future developments and applications. (c) 2015 Elsevier Ltd. All rights reserved.