Throughout history, we have looked at Nature to discover and copy pharmaceutical solutions to prevent and heal diseases. Due to the advances in metabolic engineering and the production of pharmaceutical proteins in different host cells, we have moved from mimicking Nature to the delicate engineering of cells and proteins. We can now produce novel drug molecules which are fusions of small chemical drugs and proteins. Currently we are at the brink of yet another step to venture beyond Nature’s border with the use of unnatural amino acids and manufacturing without the use of living cells using cell-free systems. In this review, we summarize the progress and limitations of the last decades in the development of pharmaceutical protein development, production in cells, and cell-free systems. We also discuss possible future directions of the field.