The determination of the best flowsheet and the development of a conceptual design of a chemical reaction-separation process is a complex task. Although model-based methods for process design have been proposed in the last decades, only a few contributions address the simultaneous design and optimization of integrated reaction-separation processes. This paper presents a systematic and optimization-based approach for the design of such processes. Shortcut methods are utilized to screen alternative flowsheet structures. For the most promising alternatives a rigorous optimization of the entire flowsheet is executed to determine the best alternative. The incremental refinement of this framework allows for the systematic generation and numerically robust evaluation of every reaction-separation process. Consequently, it helps to shorten the time for developing new and innovative processes and improves the chances to find the best process design. The suggested methodology is illustrated by means of a case study considering ethyl tert-butyl ether (ETBE) production. (C) 2015 Elsevier Ltd. All rights reserved.