The arrest of protein synthesis caused when ribosomes stall on an mRNA lacking a stop codon is a deadly risk for all cells. In bacteria, trans-translation is the principal and most sophisticated quality control mechanism for solving this problem. Trans-translation occurs because of the synergistic action of two main partners, transfer-messenger RNA (tmRNA) and small protein B (SmpB). Considering that trans-translation is absent in eukaryotes, it is an especially promising target for novel antimicrobial compounds. Here, I will present our most recent structural studies of trans-translation using cryo-electron microscopy. They allow us to describe the mechanism at the molecular level, shedding light on the movements of the tmRNA-SmpB complex in the ribosome and explaining why the process does not interfere with canonical translation. They also permit, thanks rational drug design, to design new molecules targeting the interactions between tmRNA, SmpB, and the ribosome from pathogenic bacteria implicated in antibiotic resistance (ESKAPEE group). We can hope that the groundwork already laid will soon allow the development of potent anti trans-translation molecules and respond to the increasingly urgent antibiotic resistance emergency.​