In recent years, cell-free systems (CFS) has emerged as a powerful technology to satisfy the growing demand for simple and efficient protein production as industrial processes, especially in case of biopharmaceuticals products. Very significant costs reduction, reaction scale (reached the 100 liter recently) and well-controlled reactions conditions are among the major advantages for this production platform compared to in vivo systems. In spite of those promising aspects, CFS has several hurdles, some of them have previously limited their use as a protein production technology. These obstacles have included short reaction durations of active protein synthesis, low protein production rates, and a limited ability to correctly fold proteins containing multiple disulfide bonds. However, technical advances in the last decade have addressed these limitations and revitalized CFS systems to meet the increasing demands for biopharmaceutical synthesis. This presentation comprises an overview of the CFS technology, as well as shows major advantages and challenges that should be overcome. Additionally, a comparison of systems supported on prokaryotic or several eukaryotic lysates is displayed. Finally, a number of examples of biomolecules produced by different CFS strategies are discussed.