AbstractThe bottom‐up fabrication of synthetic cells (protocells) from molecules and materials, is a major challenge of modern chemistry. A significant breakthrough has been the engineering of protocells capable of chemical communication using bio‐derived molecules and ex situ stabilised cell machineries. These, however, suffer from short shelf‐lives, high costs, and require mild aqueous conditions. In this Concept Article we analyse the chemistry at the heart of protocell communication to highlight new opportunities for synthetic chemists in protocell engineering. Specifically, we (i) categorise the main bio‐derived chemical communication machineries in enzyme cascades, DNA strand displacement, and gene‐mediated communication; (ii) review the chemistries of these signal transduction machineries; and (iii) introduce new types of bio‐inspired, fully synthetic artificial enzymes to replace their natural counterparts. Developing protocells that incorporate synthetic analogues of bio‐derived signal transduction machineries will improve the robustness, stability, and versatility of protocells, and broaden their applications to highly strategic fields such as photocatalysis and fine chemicals production.