The production of chemicals from biogenic resources is widely performed using microorganisms. These often do not meet the requirements of technical processes due to the narrow limits of microbial physiology. As a consequence, alternatives are sought. Cell-free enzymatic reaction cascades were recently proposed as next-generation bioproduction systems. Here, we address problems of microbial systems, show potential advantages of cell-free concepts and give an overview over the state of the technology. Furthermore, we address current challenges of the cell-free strategy and give an outlook on future developments.